EP4049657A1

EP4049657A1 - Modified release formulations of pridopidine

Info

Publication number: EP4049657A1
Application number: EP22163271.4A
Authority: EP
Inventors: Daniella Licht; Ioana Lovinger; Laura Yehudit Guilatt; Merav Bassan
Original assignee: Prilenia Neurotherapeutics Ltd
Current assignee: Prilenia Neurotherapeutics Ltd
Priority date: 2014-01-22
Filing date: 2015-01-21
Publication date: 2022-08-31
Also published as: EP3096759B1; JP6949487B2; PE20161220A1; CL2016001874A1; JP7266298B2; KR102479759B1; TW201605446A; IL246598B; US20240041855A1; CA2937243A1; PL3096759T3; CA2937243C; UY35962A; MX2016009427A; IL246598A0; IL280485B2; EP3096759A4; EP3096759A1; DK3096759T3; JP2020023518A

Abstract

A modified release solid oral dosage form comprising a therapeutically effective amount of Pridopidine or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable rate controlling excipient at about 30% to 50% by weight of the dosage form.

Description

This application claims priority of U.S. Provisional Application No. 62/050,626, filed September 15, 2014 , and U.S. Provisional Application No. 61/930,358, filed January 22, 2014 , the entire contents of which are hereby incorporated by reference herein.
Throughout this application, various publications are referred by first author and year of publication. Full citations for these publications are presented in a section entitled References immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which the invention relates.

BACKGROUND OF THE INVENTION

Pridopidine (Huntexil) is a unique compound developed for the treatment of patients with motor symptoms associated with Huntington's disease. Its chemical name is 4-(3-(Methylsulfonyl)phenyl)-1-propylpiperidine, and its Chemical Registry number is 882737-42-0 (U.S. Publication No. US-2013-0267552-A1 ). Processes of synthesis of pridopidine and a pharmaceutically acceptable salt thereof are disclosed in U.S. Patent No. 7,923,459 . U.S. Patent No. 6,903,120 claims Pridopidine for the treatment of Parkinson's disease, dyskinesias, dystonias, Tourette's disease, iatrogenic and non-iatrogenic psychoses and hallucinoses, mood and anxiety disorders, sleep disorder, autism spectrum disorder, ADHD, Huntington's disease, age-related cognitive impairment, and disorders related to alcohol abuse and narcotic substance abuse.

BRIEF SUMMARY OF THE INVENTION

This invention provides a modified release solid oral dosage form comprising a therapeutically effective amount of Pridopidine or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable rate controlling excipient, wherein the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a Mean C_max of about 1,400 ng/ml or less.
This invention also provides a modified release solid oral dosage form comprising a therapeutically effective amount of Pridopidine or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable rate controlling excipient, and wherein the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a C_max from about 244 ng/ml to about 1002 ng/ml when given as single dose and from about 244 ng/ml to about 1568 ng/ml when given at steady state.
This invention also provides a modified release solid oral dosage form comprising a therapeutically effective amount of Pridopidine or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable rate controlling excipient, and wherein the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a C_max which is lower than a C_max resulting from the b.i.d. administration of an immediate release solid oral dosage form which contains:

a) half the amount of the Pridopidine or a pharmaceutically acceptable salt thereof or
b) between 10% and 49% of the amount of the Pridopidine or a pharmaceutically acceptable salt thereof.

The subject invention also provides a pharmaceutical formulation comprising the modified release solid oral dosage form, and one or more pharmaceutically acceptable carriers or excipients.
The subject invention also provides the modified release solid oral dosage form or pharmaceutical formulation for use in the treatment of Huntington's Disease, Parkinson's disease, iatrogenic and non-iatrogenic Parkinsonism, dyskinesias, dystonias, Tourette's disease, iatrogenic and non-iatrogenic psychoses and hallucinoses, schizophrenia disorder or schizophreniform disorder, mood and anxiety disorders, manodepressive illness, depression, obsessive-compulsive disease, a sleep disorder, autism spectrum disorder, ADHD, age-related cognitive impairment, abuse of alcohol and substances used as narcotics, Alzheimer's disease or Retts syndrome.
The subject invention also provides a method of treating a subject afflicted with a condition selected from Huntington's Disease, Parkinson's disease, iatrogenic and non-iatrogenic Parkinsonism, dyskinesias, dystonias, Tourette's disease, iatrogenic and non-iatrogenic psychoses and hallucinoses, schizophrenia disorder or schizophreniform disorder, mood and anxiety disorders, manodepressive illness, depression, obsessive-compulsive disease, a sleep disorder, autism spectrum disorder, ADHD, age-related cognitive impairment, abuse of alcohol and substances used as narcotics, Alzheimer's disease and Retts syndrome, wherein the method comprises administering the modified release solid oral dosage form or pharmaceutical formulation to the subject in need thereof.
The invention also provides a method of treating an individual afflicted with a neurodegenerative disease or a disease related to dopamine, comprising once daily administration of the modified release solid oral dosage form or pharmaceutical formulation.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

Figure 1:: Pridopidine geometric mean plasma concentrations versus time from Example 1.
Figure 2:: Observed and predicted relation between pridopidine plasma levels and ΔΔQTcF; the line represents population mean predictions.
Figure 3:: In vitro dissolution rates of the dosage forms MR-1, MR-2 and MR-3.
Figure 4:: Plasma concentration-time profiles of pridopidine after single dose b.i.d. administration: GastroPlus Method validation: Simulation single dose 22 mg IR pridopidine, and comparison to data from study. Figure 4a is simulated data and Figure 4b is data from study.
Figure 5:: Plasma concentration-time profiles of pridopidine after multiple dose b.i.d. administration: GastroPlus Method validation: Simulation of (steady state) pharmacokinetic (PK) profile following 45 mg bid IR pridopidine, and comparison to data from study. Figure 5a is simulated data and Figure 5b is data from study.
Figure 6:: (a-b) Mean plasma level curves of pridopidine after oral administration of pridopidine as various MR and reference IR formulations, 0-12h period (a) and semi-logarithmic presentation (b).

DETAILED DESCRIPTION OF THE INVENTION

This invention provides a modified release solid oral dosage form comprising a therapeutically effective amount of Pridopidine or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable rate controlling excipient, wherein the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a Mean C_max of about 1,400 ng/ml or less.
In an embodiment, the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a Mean C_max of about 1,157 ng/ml or less.
In an embodiment, the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a Mean C_max of about 906 ng/ml or less.
In an embodiment, the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a Mean C_max of about 499 ng/ml or less.
In an embodiment, the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a Mean C_max of about 718 ng/ml or less measured after single dose administration.
In an embodiment, the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a Mean C_max of about 486 ng/ml or less measured after single dose administration.
In an embodiment, the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a Mean C_max of about 327 ng/ml or less measured after single dose administration.
In an embodiment, the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a C_max from about 382 ng/ml to about 1,568 ng/ml.
In an embodiment, the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a C_max from about 244 ng/ml to about 1,002 ng/ml. In another embodiment, the solid oral dosage form provides an in vivo plasma profile having a C_max between 244 ng/ml and 813 ng/ml. In another embodiment, the solid oral dosage form provides an in vivo plasma profile having a C_max between 493 ng/ml and 1,002 ng/ml. In an embodiment, the solid oral dosage form provides an in vivo plasma profile having a C_max between 324 ng/ml and 813 ng/ml. In an embodiment, the solid oral dosage form provides an in vivo plasma profile having a C_max between 871 ng/ml and 1,568 ng/ml.
In an embodiment, the solid oral dosage form provides an in vivo plasma profile having a C_max between 382 ng/ml and 1,287 ng/ml.
In an embodiment, the solid oral dosage form provides an in vivo plasma profile having a C_max between 639 ng/ml and 1,287 ng/ml.
In an embodiment, the Mean AUC_tau is about 5,253 ng h/ml or more. In another embodiment, the Mean AUC_tau is about 7,178 ng h/ml or more. In another embodiment, the Mean AUC_tau is about 14,185 ng h/ml or more. In another embodiment, the Mean AUC_tau is about 18,065 ng h/ml or more.
In an embodiment, the AUC_0-inf is about 2,249 ng h/ml or more. In another embodiment, the Mean AUC_0-inf is about 5,043 ng h/ml or more. In another embodiment, the Mean AUC_0-inf is about 7,897 ng h/ml or more. In another embodiment, the Mean AUC_0-inf is about 13,594 ng h/ml or more.
In an embodiment, the dosage form comprises from about 22.5mg to about 350mg Pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form comprises from about 45mg to about 300mg Pridopidine or a pharmaceutically acceptable salt thereof.
In another embodiment, the dosage form comprises from about 90 to about 250mg Pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form comprises at least about 90mg Pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form comprises at least about 100mg Pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form comprises at least about 125mg Pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form comprises at least about 135mg Pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form comprises at least about 150mg Pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form comprises at least about 180mg Pridopidine or a pharmaceutically acceptable salt thereof or more. In another embodiment, the dosage form comprises at least about 200mg Pridopidine or a pharmaceutically acceptable salt thereof or more. In another embodiment, the dosage form comprises at least about 225mg Pridopidine or a pharmaceutically acceptable salt thereof or more. In an embodiment, the dosage form comprises at least about 250mg Pridopidine or a pharmaceutically acceptable salt thereof or more. In another embodiment, the dosage form comprises at least about 315mg Pridopidine or a pharmaceutically acceptable salt thereof or more. In another embodiment, the dosage form comprises about 90mg Pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form comprises about 100mg Pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form comprises about 125mg Pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form comprises about 135mg Pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form comprises about 150mg Pridopidine or a pharmaceutically acceptable salt thereof.
In another embodiment, the dosage form comprises about 180mg Pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form comprises about 200mg Pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form comprises about 225mg Pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form comprises about 250mg Pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the dosage form comprises about 315mg Pridopidine or a pharmaceutically acceptable salt thereof.
In an embodiment, the in vivo plasma profile is measured at steady state.
In an embodiment, the in vivo plasma profile is measured after single dose administration.
This invention also provides a modified release solid oral dosage form comprising a therapeutically effective amount of Pridopidine or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable rate controlling excipient, and wherein the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a Mean C_max which is lower than a Mean C_max resulting from the b.i.d. administration of an immediate release solid oral dosage form which contains

a) half the amount of the Pridopidine or a pharmaceutically acceptable salt thereof or
b)between 10% and 49% of the amount of the Pridopidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is more than 45 mg of Pridopidine. In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 90 mg of Pridopidine and the immediate release dosage form contains about 45 mg of Pridopidine. In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 100 mg of Pridopidine and the immediate release solid oral dosage form contains about 45 mg of Pridopidine. In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 125 mg of Pridopidine and the immediate release solid oral dosage form contains about 45 mg of Pridopidine. In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 135 mg of Pridopidine and the immediate release solid oral dosage form contains about 45 mg of Pridopidine. In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 135 mg of Pridopidine and the immediate release solid oral dosage form contains about 67.5 mg of Pridopidine. In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 150 mg of Pridopidine and the immediate release solid oral dosage form contains about 45 mg of Pridopidine. In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 150 mg of Pridopidine and the immediate release solid oral dosage form contains about 67.5 mg of Pridopidine. In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 180 mg of Pridopidine and the immediate release solid oral dosage form contains about 45 mg of Pridopidine.
In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 180 mg of Pridopidine and the immediate release solid oral dosage form contains about 67.5 mg of Pridopidine. In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 180 mg of Pridopidine and the immediate release solid oral dosage form contains about 90 mg of Pridopidine. In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 200 mg of Pridopidine and the immediate release solid oral dosage form contains about 45 mg of Pridopidine. In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 200 mg of Pridopidine and the immediate release solid oral dosage form contains about 67.5 mg of Pridopidine. In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 200 mg of Pridopidine and the immediate release solid oral dosage form contains about 90 mg of Pridopidine. In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 225 mg of Pridopidine and the immediate release solid oral dosage form contains about 45 mg of Pridopidine. In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 225 mg of Pridopidine and the immediate release solid oral dosage form contains about 67.5 mg of Pridopidine.
In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 225 mg of Pridopidine and the immediate release solid oral dosage form contains about 90 mg of Pridopidine. In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 225 mg of Pridopidine and the immediate release solid oral dosage form contains about 112.5 mg of Pridopidine. In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 250 mg of Pridopidine and the immediate release solid oral dosage form contains about 45 mg of Pridopidine. In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 250 mg of Pridopidine and the immediate release solid oral dosage form contains about 67.5 mg of Pridopidine. In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 250 mg of Pridopidine and the immediate release solid oral dosage form contains about 90 mg of Pridopidine. In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 250 mg of Pridopidine and the immediate release solid oral dosage form contains about 112.5 mg of Pridopidine. In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 315 mg of Pridopidine and the immediate release solid oral dosage form contains about 45 mg of Pridopidine. In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 315 mg of Pridopidine and the immediate release solid oral dosage form contains about 67.5 mg of Pridopidine. In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 315 mg of Pridopidine and the immediate release solid oral dosage form contains about 90 mg of Pridopidine. In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 315 mg of Pridopidine and the immediate release solid oral dosage form contains about 112.5 mg of Pridopidine. In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 315 mg of Pridopidine and the immediate release solid oral dosage form contains about 157.5 mg of Pridopidine
In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is about 90 mg. In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is about 100 mg. In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is about 125 mg. In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is about 135 mg. In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is about 150 mg. In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is about 180 mg. In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is about 200 mg. In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is about 225 mg. In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is about 250 mg. In another embodiment, the amount of Pridopidine or a pharmaceutically acceptable salt thereof is about 315 mg.
In an embodiment, the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a Mean AUC_tau which is at least about 50% of the Mean AUC_tau provided by the b.i.d. administration of an immediate release solid oral dosage form which contains half the amount of the Pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a Mean AUC_tau which is at least about 60% of the Mean AUC_tau provided by the b.i.d. administration of an immediate release solid oral dosage form which contains half the amount of the Pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a Mean AUC_tau which is at least about 70% of the Mean AUC_tau provided by the b.i.d. administration of an immediate release solid oral dosage form which contains half the amount of the Pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a Mean AUC_tau which is at least about 80% of the Mean AUC_tau provided by the b.i.d. administration of an immediate release solid oral dosage form which contains half the amount of the Pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a Mean AUC_tau which is at least about 90% of the Mean AUC_tau provided by the b.i.d. administration of an immediate release solid oral dosage form which contains half the amount of the Pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a Mean AUC_tau which is at least about 95% of the Mean AUC_tau provided by the b.i.d. administration of an immediate release solid oral dosage form which contains half the amount of the Pridopidine or a pharmaceutically acceptable salt thereof.
In an embodiment, the b.i.d. administration of an immediate release solid oral dosage form has a time interval between doses of 5-10 hours. In another embodiment, the b.i.d. administration of an immediate release solid oral dosage form has a time interval between doses of 6-8 hours. In another embodiment, the b.i.d. administration of an immediate release solid oral dosage form has a time interval between doses of 6.5 hours. In another embodiment, the b.i.d. administration of an immediate release solid oral dosage form has a time interval between doses of 7 hours.
In an embodiment, the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a Mean C_max which is reduced by a percentage compared to the Mean C_max resulting from the b.i.d. administration of an immediate release dosage form which contains half the amount of the Pridopidine or a pharmaceutically acceptable salt thereof wherein the percentage is at least 5%. In another embodiment, the percentage is at least 10%. In another embodiment, the percentage is at least 20%. In another embodiment, the percentage is at least 30%. In another embodiment, the percentage is at least 40%. In another embodiment, the percentage is at least 50%. In another embodiment, the percentage is at least 60%. In another embodiment, the percentage is at least 70%. In another embodiment, the percentage is between 10% and 60%. In another embodiment, the percentage is between 20% and 50%. In another embodiment, the percentage is about 25%. In another embodiment, the percentage is about 35%. In another embodiment, the percentage is about 50%.
In an embodiment, the Mean time required to reach the maximal plasma, serum or blood concentration of the drug, following administration of the drug is more than 2 hours. In another embodiment, the Mean time required to reach the maximal plasma, serum or blood concentration of the drug, following administration of the drug is more than 4 hours.
In an embodiment, the pharmaceutically acceptable salt of Pridopidine is hydrochloride salt.
In another embodiment, the in vivo plasma profile is measured at steady state.
In an embodiment, the in vivo plasma profile is measured after single dose administration.
In an embodiment, the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a mean AUC_0-inf which is at least about 50% of the mean AUC_0-inf provided by the b.i.d. administration of an immediate release solid oral dosage form which contains half the amount of the Pridopidine or a pharmaceutically acceptable salt thereof.
In an embodiment, the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a mean AUC_0-inf which is at least about 55% of the mean AUC_0-inf provided by the b.i.d. administration of an immediate release solid oral dosage form which contains half the amount of the Pridopidine or a pharmaceutically acceptable salt thereof.
In an embodiment, the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a mean AUC_0-inf which is at least about 75% of the mean AUC_0-inf provided by the b.i.d. administration of an immediate release solid oral dosage form which contains half the amount of the Pridopidine or a pharmaceutically acceptable salt thereof.
In an embodiment, the solid oral dosage form releases not more than 50% of pridopidine after 1 hour when the oral dosage form is placed in a basket apparatus in 500mL of HCl 0.1N at a temperature of 37°C rotating at 100 revolutions per minute. In an embodiment, the solid oral dosage form releases not more than 75% of pridopidine after 3 hours when the oral dosage form is placed in a basket apparatus in 500mL of HCl 0.1N at a temperature of 37°C rotating at 100 revolutions per minute for 120 minutes and then in buffer phosphate having a pH 6.8, for 12 hours. In another embodiment, the solid oral dosage form releases not less than 80% of pridopidine after 10 hours when the oral dosage form is placed in a basket apparatus in 500mL of HCl 0.1N at a temperature of 37°C rotating at 100 revolutions per minute for 120 minutes and then in buffer phosphate having a pH 6.8, for 12 hours. In another embodiment, the solid oral dosage form releases not more than 30% of pridopidine after 2 hours when the oral dosage form is placed in a basket apparatus in 500mL of HCl 0.1N at a temperature of 37°C rotating at 100 revolutions per minute for 120 minutes and then in buffer phosphate having a pH 6.8, for 12 hours. In another embodiment, the solid oral dosage form releases not more than 50% of pridopidine after 4 hours when the oral dosage form is placed in a basket apparatus in 500mL of HCl 0.1N at a temperature of 37°C rotating at 100 revolutions per minute for 120 minutes and then in buffer phosphate having a pH 6.8, for 12 hours. In another embodiment, the solid oral dosage form releases not more than 65% of pridopidine after 6 hours when the oral dosage form is placed in a basket apparatus in 500mL of HCl 0.1N at a temperature of 37°C rotating at 100 revolutions per minute for 120 minutes and then in buffer phosphate having a pH 6.8, for 12 hours. In another embodiment, the solid oral dosage form releases not less than 75% of pridopidine after 12 hours when the oral dosage form is placed in a basket apparatus in 500mL of HCl 0.1N at a temperature of 37°C rotating at 100 revolutions per minute for 120 minutes and then in buffer phosphate having a pH 6.8, for 12 hours.
In an embodiment, the dosage form is in the form of a capsule. In another embodiment, the dosage form is in the form of a tablet.
In an embodiment, the rate controlling excipient is a polymeric material.
In an embodiment, the polymer can be hydrophobic or hydrophilic. In an embodiment, the polymeric material is selected from a group consisting of: hydrogenated castor oil, polyethylene oxide, ethyl cellulose hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinyl alcohol (PVA), vinyl alcohol polymer, polycrylates, polymethacrylates, ethyl acrylate-methyl methacrylate copolymers, glyceryl monostearate, and mixtures thereof.
In an embodiment, the rate controlling excipient is a combination of two or more polymeric materials, preferably wherein rate controlling excipient is a combination of at least a hydroxypropyl methylcellulose (HPMC) and hydrogenated castor oil.
In an embodiment, the polymeric material is hydroxypropyl methylcellulose. In another embodiment, the polymeric material is hydrogenated castor oil.
In an embodiment, the total amount of the rate controlling excipients is from about 8% to about 70% of the total weight of the dosage form, from about 10% to about 50% of the total weight of the dosage form, or from about 20% to about 50% of the total weight of the dosage form, from about 30% to about 50% or from about 30% to about 40% of the total weight of the dosage form.
In an embodiment, the polymeric material is between 10% and 50% by weight of the solid oral dose form.
In an embodiment, the polymeric material is between 20% and 50% by weight of the solid oral dose form. In another embodiment, the polymeric material is between 30% and 50% by weight of the solid oral dose form. In another embodiment, the polymeric material is between 30% and 40% by weight of the solid oral dose form. In another embodiment, the polymeric material is between 35% and 40% by weight of the solid oral dose form. In another embodiment, the polymeric material is at least 10% by weight of the solid oral dose form. In another embodiment, the polymeric material is at least 20% by weight of the solid oral dose form. In another embodiment, the polymeric material is at least 25% by weight of the solid oral dose form. In another embodiment, the polymeric material is at least 30% by weight of the solid oral dose form. In another embodiment, the polymeric material is at least 35% by weight of the solid oral dose form. In another embodiment, the polymeric material is at least 40% by weight of the solid oral dose form. In another embodiment, the polymeric material is about 37% by weight of the solid oral dose form. In another embodiment, the polymeric material is about 38% by weight of the solid oral dose form. In another embodiment, the polymeric material is about 40% by weight of the solid oral dose form.
In an embodiment, the modified release solid oral dosage form further comprises an ethylcellulose.
In an embodiment, the total amount of the ethylcellulose is from about 0.5% to about 10% of the total weight of the dosage form, from about 0.5% to about 7.2% of the total weight of the dosage form, from about 1.0% to about 5% of the total weight of the dosage form, from about 1.0% to about 3.0% of the total weight of the dosage form, from about 1.5% to about 3.0% of the total weight of the dosage form, or from about 1.5% to about 2.4% of the total weight of the dosage form.
In another embodiment, the ethylcellulose is about 1.5% by weight of the solid oral dose form. In an embodiment, the ethylcellulose is about 3.0% or about 2.4% by weight of the solid oral dose form.
In another embodiment, the polymeric material is hydroxypropyl methylcellulose, and wherein the hydroxypropyl methylcellulose is about 38% by weight of the solid oral dose form.
In an embodiment, the polymeric material is hydrogenated castor oil, and wherein the hydrogenated castor oil is about 38% by weight of the solid oral dose form.
In an embodiment, the polymeric material is hydroxypropyl methylcellulose, wherein the hydroxypropyl methylcellulose is about 37% by weight of the solid oral dose form, and wherein the ethylcellulose is between about 1.5% and about 3.0% by weight of the solid oral dose form.
In an embodiment, the weight ratio of the Pridopidine or the pharmaceutically acceptable salt thereof to the rate controlling excipient is from about 0.2:1 to about 1:1, preferably from about 0.3:1 to about 0.8:1, more preferably about 0.5:1 to about 0.7:1.
In an embodiment, the modified release solid oral dosage form further comprising a mucoadhesive.
In an embodiment, the mucoadhesive is selected from the group consisting of water soluble or water insoluble hydrophilic polymers, polymers that have swellable networks, hydrogels, and polymers with groups that can cross-link with other polymers or with a mucous membrane, preferably the mucoadhesive is polyethylene oxide.
In an embodiment, the Pridopidine or the pharmaceutically acceptable salt thereof comprises from about 15% to about 60% by weight of the dosage form. In another embodiment, the Pridopidine or the pharmaceutically acceptable salt thereof comprises from about 25% to about 50% by weight of the dosage form.
In an embodiment, the Pridopidine or the pharmaceutically acceptable salt thereof comprises about 25% by weight of the dosage form.
The subject invention also provides a pharmaceutical formulation comprising the modified release solid oral dosage form, and one or more pharmaceutically acceptable carriers or excipients.
In an embodiment, the pharmaceutically acceptable carriers or excipients are selected from a group consisting of: binder, filler, plasticizer, glidant and lubricant and mixtures thereof.
In an embodiment, the binder is selected from a group consisting of: starch, pregeletinized starch, polyethylene oxide, cellulose polymers, hydroxypropylmethyl cellulose, hydroxypropylcellulose, methylcellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol and mixtures thereof.
In an embodiment, the filler is selected from a group consisting of: microcrystalline cellulose, sugar spheres, lactose, sorbitol, dextrose, sucrose, mannitol, dibasic or tribasic calcium phosphate, calcium sulfate, starch, retalac and mixtures thereof.
In an embodiment, the filler is microcrystalline cellulose and is a silicified microcrystalline cellulose.
In an embodiment, the filler is lactose. In another embodiment, the filler is a mixture of microcrystalline cellulose and lactose, and wherein the microcrystalline cellulose and is a silicified microcrystalline cellulose.
In an embodiment, the filler is between 5% and about 64% by weight of the solid oral dose form, between 10% and about 50% by weight of the solid oral dose form, between 15% and about 45% by weight of the solid oral dose form, between 20% and 40% by weight of the solid oral dose form, about 34% by weight of the solid oral dose form, about 16% by weight of the solid oral dose form, about 17% by weight of the solid oral dose form or about 18% by weight of the solid oral dose form.
In an embodiment, the filler is a mixture of silicified microcrystalline cellulose and lactose and wherein silicified microcrystalline cellulose is about 16% by weight of the solid oral dose form and lactose is about 17% or about 18% by weight of the solid oral dose form. In an embodiment, the plasticizer is selected from a group consisting of: polyethylene glycol, triethyl citrate, tributyl citrate, glycerin, dibutyl sebacate, triacetin, diethylphthalat and mixtures thereof.
In an embodiment, the glidant is selected from a group consisting of: starch, pregelatinized starch, silicone dioxide, colloidal silicone dioxide, talc and mixtures thereof.
In an embodiment, the glidant is colloidal silicone dioxide.
In an embodiment, the glidant is between 0.2% and about 4% by weight of the solid oral dose form, between 0.4% and about 3% by weight of the solid oral dose form, or between 0.43% and about 2.0% by weight of the solid oral dose form.
In an embodiment, the glidant is between 1.7% and about 4% by weight of the solid oral dose form, between 1.7% and about 3% by weight of the solid oral dose form, between 1.7% and about 2.0% by weight of the solid oral dose form, between 1.7% and 1.8% by weight of the solid oral dose form, about 1.7% by weight of the solid oral dose form or about 1.8% by weight of the solid oral dose form.
In an embodiment, the lubricant is selected from a group consisting of: sodium stearyl fumarate, stearic acid, magnesium stearate, calcium stearate, zinc stearate, talc, glyceryl behenate, glyceryl monostearate, and mixtures thereof.
In an embodiment, the lubricant is magnesium stearate.
In an embodiment, the lubricant is between 0.3% and about 4% by weight of the solid oral dose form, between 0.5% and about 3% by weight of the solid oral dose form, or between 1.1% and about 2.0% by weight of the solid oral dose form.
In an embodiment, the lubricant is between 1.7% and about 4% by weight of the solid oral dose form, between 1.7% and about 3% by weight of the solid oral dose form, between 1.7% and about 2.3% by weight of the solid oral dose form, between 1.8% and about 2.2% by weight of the solid oral dose form or about 2% by weight of the solid oral dose form.
The subject invention also provides the modified release solid oral dosage form or pharmaceutical formulation for use in the treatment of Huntington's Disease, Parkinson's disease, iatrogenic and non-iatrogenic Parkinsonism, dyskinesias, dystonias, Tourette's disease, iatrogenic and non-iatrogenic psychoses and hallucinoses, schizophrenia disorder or schizophreniform disorder, mood and anxiety disorders, manodepressive illness, depression, obsessive-compulsive disease, a sleep disorder, autism spectrum disorder, ADHD, age-related cognitive impairment, abuse of alcohol and substances used as narcotics, Alzheimer's disease or Retts syndrome.
The subject invention also provides a method of treating a subject afflicted with a condition selected from Huntington's Disease, Parkinson's disease, iatrogenic and non-iatrogenic Parkinsonism, dyskinesias, dystonias, Tourette's disease, iatrogenic and non-iatrogenic psychoses and hallucinoses, schizophrenia disorder or schizophreniform disorder, mood and anxiety disorders, manodepressive illness, depression, obsessive-compulsive disease, a sleep disorder, autism spectrum disorder, ADHD, age-related cognitive impairment, abuse of alcohol and substances used as narcotics, Alzheimer's disease and Retts syndrome, wherein the method comprises administering the modified release solid oral dosage form or pharmaceutical formulation to the subject in need thereof.
In an embodiment, two doses of the modified release solid oral dosage form or pharmaceutical formulation are administered to the individual and the interval between the two doses is about 24 hours.
In an embodiment, the subject is a human patient.
In an embodiment, the dosage form has the following in vivo plasma pridopidine concentration profile concentrations at steady state: a C_max from about 499 ng/ml to about 1400 ng/ml, a mean C_max from about from about 499 ng/ml to about 1157 ng/ml, or a mean C_max from about 906 ng/ml to about 1157 ng/ml. The invention also provides a method of treating an individual afflicted with a neurodegenerative disease or a disease related to dopamine, comprising once daily administration of the modified release solid oral dosage form or pharmaceutical formulation.
In an embodiment, the modified release solid oral dosage form or pharmaceutical formulation is adapted for once daily administration.
For the foregoing embodiments, each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments. In addition, the elements recited in pharmaceutical composition embodiments can be used in the method and use embodiments described herein.

Terms:

As used herein, the term "C" refers to the plasma/serum/blood concentration of an active pharmaceutical ingredient, or drug, following administration of the drug, e.g. Pridopidine, or a pharmaceutically acceptable salt thereof, in a biological sample, such as a patient sample (e.g., blood, plasma, serum, and cerebrospinal fluid). The concentration of the drug in the biological sample may be determined by any standard assay method known in the art. The term C includes such concentrations measurements as the C_min, C_max, and Css (average steady state concentration), and allows calculation of PK parameters such as AUC. Typically the term C refers to the plasma, serum or blood concentration.
As used herein, steady state refers to the situation in which the amount of drug eliminated at each dose interval equals the dose for that interval. In an embodiment, steady state administration as used herein is reached after 7 days. In an embodiment, steady state administration as used herein is reached after 9 days. In an embodiment, steady state administration as used herein is reached after 14 days.
As used herein, the term "C_max" refers to the maximum plasma, serum or blood concentration of a drug, following administration of the drug, e.g. Pridopidine, or a pharmaceutically acceptable salt thereof. C_max measured at steady state is sometimes referred as to Cmax,ss. "Mean C_max" "_Cmax,ss," and "mean C_max0-t" are the mean of the respective C_max measured in a sample of patients. In an embodiment, the sample of patients includes four patients or more. Preferably, the sample should include ten patients or more.
As used herein, the term "C_min" refers to the minimum plasma, serum or blood concentration of a drug, following administration of the drug, e.g. Pridopidine, or a pharmaceutically acceptable salt thereof. C_min measured at steady state is sometimes referred as to C_min,ss.
As used herein, the term "T_max" refers to the time required to reach the maximal plasma, serum or blood concentration ("C_max") of the drug, following administration of the drug, e.g. Pridopidine, or a pharmaceutically acceptable salt thereof. T_max measured at steady state is sometimes referred as to T_max,ss.
As used herein, the term "AUC" refers to the area under the plasma, serum or blood concentration versus time curve.
As used herein, the terms "AUC_t" and "AUC_0-t" refer to the area under the plasma, serum or blood concentration versus time curve wherein t is the last measured time point.
As used herein, the terms "AUC_inf", "AUC_0-inf" "AUC_∞", "AUC_{0- ∞}" and AUC_infinity refer to the area under the plasma, serum or blood concentration versus time curve extrapolated to infinity.
As used herein, the terms "AUC_tau" and "AUC_0-tau" refer to the area under the curve for a plasma, serum or blood concentration versus time curve of a drug over one dosing interval, following the administration of the drug such as Pridopidine or a pharmaceutically acceptable salt thereof. The area under the curve is measured for a time tau, where tau is the length of the dosing interval. The term AUC_tau,ss measures the exposure over the dosing interval at steady state. As use herein, tau is a 24 hours interval, this includes cases in which the drug is administered b.i.d. "Mean AUC," "Mean AUC_t," "Mean AUCo-t," "Mean AUC_inf," "Mean AUC_tau" and "Mean AUC_0-tau" are the mean of the respective AUC measured in a sample of patients. In an embodiment, the sample of patients includes four patients or more. Preferably, the sample should include ten patients or more.
As used herein, "single dose" administration means that the drug is administered over a 24 hours interval, either as once per day (qd) or twice a day (bid).
As used herein, the term "immediate release" or "IR" means that the escape or release in the body of a drug, such as Pridopidine or a pharmaceutically acceptable salt thereof, from a dosage form (tablet, capsule, pellet, etc.) occurs immediately or soon after administration, usually in minutes to a few hours. For example, 80% of drug may be dissolved over the first hour. The drug is released in a single action and the time of action of the drug is often limited.
As used herein, the term "modified release" or "MR" means that the escape or release of a drug, such as Pridopidine or a pharmaceutically acceptable salt thereof, from the dosage form (tablet, capsule, pellet, etc.) has been modified so that the release rate is slower than that in an unmodified or immediate release dosage form. Drug release takes place at a point in time after administration or for a prolonged period after administration or to a specific target in the body. Drug release may occur over several hours or over several days in order to maintain a therapeutically effective plasma concentration of the drug. Modified release encompasses delayed release (release at a time other than immediately after administration), extended release (release over a prolonged time period), sustained release (rate of drug release is sustained over a period of time), and controlled release (rate of drug release is controlled to get a particular drug concentration profile in the body).
As used herein, a slower dissolution profile is one in which the escape or release of a drug from the dosage form is slower, i.e. it takes more time for the drug to be released in a slower dissolution profile than a faster dissolution profile.
As used herein, the term "rate controlling excipient" refers to an excipient or a combination of excipients present in such amounts sufficient to reduce the rate of drug release from a dosage form, such as Pridopidine or a pharmaceutically acceptable salt thereof. A rate controlling excipient or a combination thereof controls the rate of drug release from a dosage form.
As used herein, the term "at least one pharmaceutically acceptable rate controlling excipient" or "one or more pharmaceutically acceptable rate controlling excipients" refers to the presence of one, two, three, four, or more rate controlling excipients in the dosage form.
As used herein, the term "Pridopidine" refers to Pridopidine free base. In certain embodiments, Pridopidine also includes any pharmaceutically acceptable salt, such as the HCl salt. Preferably, in any embodiments of the invention as described herein, the Pridopidine is in the form of its hydrochloride salt.
As used herein, an "amount" or "dose" of Pridopidine as measured in milligrams refers to the milligrams of Pridopidine base present in a preparation, regardless of the form of the preparation. A dosage of "90 mg Pridopidine" means the amount of Pridopidine base in a preparation is 90 mg, regardless of the form of the preparation. Thus, when in the form of a salt, e.g. a Pridopidine hydrochloride salt, the weight of the salt form necessary to provide a dose of 90 mg Pridopidine would be greater than Pridopidine mg due to the presence of the additional salt ion.
As used herein, a "unit dose", "unit doses" and "unit dosage form(s)" mean a single drug administration entity/entities.
As used herein, "about" in the context of a numerical value or range means ±10% of the numerical value or range recited or claimed.
As used herein, the term "once daily" means administering a dose once every 24 hours. As used herein, the term "QD" refers to a once daily administration.
As used herein, reference to a total weight of a dosage form refers to the total weight of a tablet (including any finishing coat), and in the case of a capsule, refers to the total weight of the capsule contents, excluding the weight of the capsule itself.
As used herein, the term "bioavailability" refers to the rate and extent to which an active pharmaceutical ingredient is absorbed from a dosage form and becomes available at the site of action.
A pharmacokinetic parameter or combinations of such parameters indicate the bioavailability of an active pharmaceutical ingredient, such as, Pridopidine following administration of Pridopidine or a pharmaceutically acceptable salt thereof. Such pharmacokinetic parameters are known to the person skilled in the art. Examples of such parameters include: C_max, AUC, AUC_tau, and T_max.
The dosage forms of the present invention are formulated such that the pridopidine or a pharmaceutically acceptable salt thereof has an in vitro dissolution profile that is slower than that for an immediate release (IR) formulation. The dosage forms of the present invention may contain immediate release, sustained or extended release or delayed release components, or combinations thereof.
The pridopidine or a pharmaceutically acceptable salt thereof, in the solid oral dosage forms of the present invention can be provided in a modified release form such as modified, controlled or extended release (ER) form, with or without an immediate release (IR) component.
Modified release dosage forms can be made by, but not limited to, making pellets of different thicknesses so that the thinnest release the drug first and the thickest last, including a slow dissolving matrix or coating, including a non-dissolving coating around a tablet or capsule with small holes to let the drug out (by diffusion or solvation), controlling release of the drug by diffusion through a coating or matrix or by erosion of the matrix or coating by a process dependent on, for example, a particular condition such as the presence of enzymes or a particular pH. Modified release dosage forms have higher amounts of the drug than the amount present in an unmodified or immediate release dosage form.
The solid oral dosage forms of the present invention include all pharmaceutically acceptable salts of pridopidine. Preferably, the pridopidine is in its hydrochloride salt form.
The modified release solid oral dosage form of the present invention is suitable for administration in a one unit dosage form. Oral dosage forms for the purpose of the present invention include capsules, tablets, pellets, granules, powders coated or uncoated and combinations thereof. Optionally, if the dosage form is a capsule, the pridopidine or a pharmaceutically acceptable salt thereof is provided in the form of coated or uncoated pellets, granules, powders, mini tablets, tablets or capsules.
As used herein, a "polymeric material" includes any polymer. Any suitable polymeric material may be used in accordance with the teachings presented herein. The polymeric material may be any suitable shape and may take any suitable form.
The dosage forms of the present invention may include a mucoadhesives to slow the passage of the dosage form through the body so that the dosage form remains in the body sufficiently long for all the Pridopidine to be released in the body.
The solid oral dosage forms of the present invention can further comprise one or more mucoadhesives. Mucoadhesives slow the passage of the dosage form through the body so that the dosage form is inside the body during the interval between administrations so that pridopidine or a pharmaceutically acceptable salt thereof is released in the body. Mucoadhesives are substances that adhere to a biological tissue for an extended period of time by interfacial forces. The biological tissue is a mucous membrane. Mucoadhesion occur when a mucoadhesive contacts and adheres to a membrane by wetting of the mucoadhesive surface or from the swelling of the mucoadhesive. Further adhesion occurs when the mucoadhesive penetrates into the crevice of the membrane surface or when the chains of the mucoadhesive interacts with those of the mucus on the membrane. Suitable mucoadhesive are polymers that are water soluble or water insoluble hydrophilic polymers, polymers that have swellable networks, hydrogels, and polymers with groups that can cross-link with other polymers or with a mucous membrane.
The modified release solid oral dosage forms of the present invention can comprise at least one mucoadhesive with or without an immediate release component. For example, the dosage forms of the present invention can comprise at least one mucoadhesive with only an extended release component.
Silicified microcrystalline cellulose may be any commercially available form of this excipient, for example Prosolv^® SMCC 90.
Hydroxypropyl methylcellulose (HPMC) may be any commercially available form of this Hydrophilic carrier, for example Methocel^™ K100 Premium CR, Methocel DC2, Benecel ME 233P.
Lactose spray dried (SD), Lactose anhydrous and Lactose monohydrate may be used interchangeable throughout this invention.
Colloidal silicon dioxide (CSD) is a fumed silica generally prepared by vapour-phase hydrolysis of a silicon compound, such as silicon tetrachloride. The product itself is usually a powder which is commercially available from a number of sources, including Degussa, Inc. (under the trade name Aerosil^®); Cabot Corporation (under the trade name Cab-O-Sil); Huber Engineered Materials (Huber GL100 and GL200); Wacker (Wacker HDK ^® ); and E.I. DuPont & Co. Colloidal silicon dioxide is also known as colloidal silica, fumed silica, light anhydrous silicic acid, silicic anhydride, and silicon dioxide fumed, among others. A variety of commercial grades of CSD are produced by varying the manufacturing process.
Ethylcellulose may be added to the formulation in the form of dispersion for example, Surelease^®.
Pregelatinized Starch may be any commercially available form of this substance, for example Starch 1500^®.
LubriTose^™ is Lactose plus between 2% and 10% Glyceryl MonoStearate (GMS), LubriTose^™ Yellow contains 10% GMS and LubriTose^™ blue contains 2% GMS.
Tablets may contain suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, melting agents, and plasticizers. For instance, for oral administration in the dosage unit form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as xylose, gelatin, agar, starch, methyl cellulose, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, microcrystalline cellulose and the like. Suitable binders include starch, gelatin, natural sugars such as corn starch, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, povidone, polyvidone, carboxymethylcellulose, hydroxypropyl cellulose, polyethylene glycol, waxes, and the like. Glidants used in these dosage forms include silicon dioxide and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, sodium benzoate, sodium acetate, stearic acid, sodium stearyl fumarate, talc and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, croscarmellose sodium, sodium starch glycolate and the like, suitable plasticizers include triacetin, triethyl citrate, dibutyl sebacate, polyethylene glycol and the like.
The modified release solid oral dosage forms of the present invention may further comprise one or more pharmaceutically acceptable carriers or excipients.
Examples of pharmaceutical acceptable excipients are fillers, binders, glidants, plasticizer and lubricants.
Tablets in accordance with this invention can be prepared by conventional mixing, comminution, and tabletting techniques that are well known in the pharmaceutical formulations industry. The modified release tablet, for example, may be obtained by direct compression by punches and dies fitted to a rotary tabletting press, ejection or compression molding, dry of wet granulation followed by compression, or forming a paste and extruding the paste into a mold or cutting the extrudate into short lengths. Preferably, the process used for preparing tablets is direct compression of the blend.
Compression can be accomplished using conventional equipment. Typically, the blend of active ingredients with or without excipients is passed through a roller apparatus for compaction. However, other means for compacting the API mixture, e.g., compaction into slugs (or "slugging"), may be used.
To achieve the desired modified release rates, the modified release dosage form may be formulated as a polymeric coating or matrix. USP #1 apparatus (basket), is the apparatus 1 described in the United States Pharmacopeia, 29th Edition, chapter 711. The apparatus may be constructed as follows:
The assembly consists of the following: a covered vessel made of glass or other inert, transparent material; a motor; a metallic drive shaft; and a cylindrical basket. The vessel is partially immersed in a suitable water bath of any convenient size or placed in a heating jacket. The water bath or heating jacket permits holding the temperature inside the vessel at 37 ± 0.5 during the test and keeping the bath fluid in constant, smooth motion. No part of the assembly, including the environment in which the assembly is placed, contributes significant motion, agitation, or vibration beyond that due to the smoothly rotating stirring element. Apparatus that permits observation of the specimen and stirring element during the test is preferable. The vessel is cylindrical, with a hemispherical bottom and with one of the following dimensions and capacities: for a nominal capacity of 1 L, the height is 160 mm to 210 mm and its inside diameter is 98 mm to 106 mm; for a nominal capacity of 2 L, the height is 280 mm to 300 mm and its inside diameter is 98 mm to 106 mm; and for a nominal capacity of 4 L, the height is 280 mm to 300 mm and its inside diameter is 145 mm to 155 mm. Its sides are flanged at the top. A fitted cover may be used to retard evaporation. The shaft is positioned so that its axis is not more than 2 mm at any point from the vertical axis of the vessel and rotates smoothly and without significant wobble. A speed-regulating device is used that allows the shaft rotation speed to be selected and maintained at the rate specified in the individual monograph, within ±4%. Shaft and basket components of the stirring element are fabricated of stainless steel type 316 or equivalent.
Unless otherwise specified in the individual monograph, use 40-mesh cloth. A basket having a gold coating 0.0001 inch (2.5 µm) thick may be used. The dosage unit is placed in a dry basket at the beginning of each test. The distance between the inside bottom of the vessel and the basket is maintained at 25 ± 2 mm during the test.

Pridopidine

Pridopidine is absorbed relatively rapidly after oral administration with t_max between 0.5 to 4 hours (Lindskov 2012). After absorption, pridopidine is eliminated partly by urinary excretion, partly by hepatic metabolism, and primarily by N-depropylation via the CYP2D6 pathway into one main inactive metabolite, 4-(3-(methylsulfonyl)phenyl)piperidine, with an elimination half-life after repeated doses of 10-14 hours. CYP2D6 polymorphisms can be classified according to one of four levels of activity: poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs). The EM phenotype is expressed by the majority of the population (around 90%). Approximately 5-10% of the Caucasian European and North American population, and 1% of Chinese, Japanese and Korean populations are PMs. PMs inherit two deficient CYP2D6 alleles and, as a result, metabolize drugs at a notably slower rate. The Ultrarapid metabolizers (UM) phenotype is caused by the duplication, multiduplication, or amplification of active CYP2D6 genes, including primarily the CYP2D6 ^∗2 allele, but also involving CYP2D6 ^∗1 and others. Individuals with the UM phenotype metabolize drugs at an ultrarapid rate. Lastly, individuals who are heterozygous for a defective CYP2D6 allele often demonstrate an IM phenotypewith a wide spectrum of metabolic activity that can range from marginally better than the PM phenotype to activity that is close to that of the EM phenotypec (Bernard 2006).
A Phase 2, Dose-Finding, Randomized, Parallel-Group, Double- Blind, Placebo-Controlled Study, Evaluating the Safety and Efficacy of Pridopidine 45 mg, 67.5 mg, 90 mg, and 112.5 mg Twice-Daily Versus Placebo for Symptomatic Treatment in Patients With Huntington's Disease is planned (Clinicaltrials.gov Clinical Trial Identifier NCT02006472). Therefore, a dosage form comprising Pridopidine at these doses with a good safety profile is desirable. In addition, a dosage form administered less frequently than twice a day would increase compliance and would be preferable for the patients and caregivers.
The present invention is illustrated by the following examples, which are not intended to limit the scope of the invention. It will be appreciated that various modifications are within the spirit and scope of the invention.

Examples

Example 1: Safety of Pridopidine Administration Following Administration of Immediate Release dosage forms.

Multiple Ascending Dose (MAD) study

In a Multiple Ascending Dose (MAD) study, thirty-six (36) healthy volunteers of both sexes (age 18-55 years) from the CYP2D6 EM genotype were randomized to 3 cohorts. Within each cohort, 9 subjects were randomized to 2 ascending doses of pridopidine b.i.d. in fixed sequence (45-67.5mg, 67.5-90mg, and 90-112.5mg), and 3 subjects to matching placebo b.i.d. treatment in both treatment periods. Each period consisted of 9 consecutive days of b.i.d. dosing (with a 6.5 hr interval between the morning and the afternoon dose) to steady state (Østerberg 2012). Pridopidine drug concentrations were monitored up to 24 hours after the first dose and single dose parameters (associated with the first 24 hours interval) were determined. The geometric mean plasma concentrations versus time during the study are presented in Figure 1.

Safety and tolerability were assessed by monitoring adverse events (AEs), measuring vital signs, electrocardiograms (ECGs), and clinical laboratory values. PK parameters of pridopidine were calculated using non-compartmental methods and summarized by descriptive statistics by treatment/dose level (Table 1A and 1B for Day 9 and Day 1 respectively). The dosing interval in this trial (tau) was defined as 24 hours.

Table 1A: Summary of pharmacokinetic parameters at steady state (mean ± SD)

N	Dose and Regimen	Mean ± SD
N	Dose and Regimen	AUCtau,ss (hr^∗ng/mL)	Cmax,ss (ng/mL)	T1/2 (h)	Tmax,ss (h) (range)
8	IR 45mg BID	7178 ±1672 5253-10458	499 ±97 382-664	10.5 ±3.05	1.5 (1.0-2.5)
16	IR 67.5mg BID	14185 ±3747 10228-21065	906 ±207 639-1287	10.4 ±2.5	2.0 (1.0-4.0)
14	IR 90mg BID	18065 ±3413 12670-24151	1157 ±190 871-1568	10.2 ±2.1	2.0 (1.0-4.0)

Table 1B: Summary of pharmacokinetic parameters after single dose administration (mean ± SD)

N	Dose and Regimen	Mean ± SD		Median
N	Dose and Regimen	AUC_0-inf (hr^∗ng/mL)	Cmax,_6.5-24 (ng/mL)	T1/2 (h) (range)	Tmax,ss (h) (range)
8	IR 45mg BID	5043 ±3276 2249-12570	327 ±99.3 244-545	6.41 (4.31-15.4)	1.0 (1.00-2.50)
16	IR 67.5mg BID	7897 ±2811 3907 -14620	486 ±116 324-813	7.40 (4.39-11.2)	1.5 (1.00-2.50)
14	IR 90mg BID	13594 ±3880 7934-22138	718 ±144 493-1002	9.00 (6.61-14.0)	1.75 (1.00-2.50)

As shown in Table 2, the adverse events, such as gastrointestinal disorders, increased in frequency with increasing doses. Psychiatric disorders were primarily observed at the 90 mg dose b.i.d., with one observation of psychiatric disorder in the 45 mg dose b.i.d.
A prolonged QT interval has been associated with increased risks for Torsade de Points. Electrocardiogram (ECG) measurements were collected at baseline (predose on the 1^st day) and serially on Day 9 (coupled to the PK samples). A high precision QT measurement technique was implemented. The primary endpoint for the QTc analysis was placebo-corrected change-from-baseline QTcF (QT corrected through the Fredericia correction;, ΔΔQTcF). The relationship between pridopidine plasma concentrations and ΔΔQTcF was quantified using a linear mixed-effects modeling approach.
The results showed a concentration-dependent effect of pridopidine on ΔΔQTcF, suggesting that higher concentrations result in longer QT prolongation. The estimated population intercept and slope was 3.82 ms and 0.0185 ms per ng/mL (CI: 0.0139 to 0.0231), respectively (Figure 2).

Summary of the Results of Example 1

The results as presented in Table 1A showed that a mean Cmax,ss as high as about 1157 ng/ml (with a maximal measured value of 1568 ng/ml), can be safely administered to humans. The results presented in Table 1A also shows that the 45 mg IR bid administration resulted in a mean Cmax,ss value of 499 ng/ml and mean AUCtau,ss value (tau defined as a 24 hours interval covering two doses) of 7178 hr^∗ng/mL; these values are known to show therapeutic benefit. The range of AUCtau,ss resulting from the administration of 45-90mg b.i.d was 5253-24151 hr^∗ng/mL. Similarly, the results as presented in Table 1B showed that a mean C_max as high as about 718 ng/ml at day 1 (with a maximal measured value of 1002 ng/ml), can be safely administered to humans. The results presented in Table 1B also shows that the 45 mg IR bid administration resulted in a mean C_max value of 327 ng/ml and mean AUC_{0- inf} value of 5043 hr^∗ng/mL. The range of AUCo- _inf resulting from the administration of 45-90mg b.i.d was 2249-22138 hr^∗ng/mL.
Additionally, the results presented in Figure 2 shows that a concentration as high as 1400 ng/ml can be considered safe related to the potential prolongation of the QT interval.
The results in Tables 1A, 1B, and 2 show that when certain dosages of pridopidine are administered, there is a risk of increasing the frequency of adverse events in comparison to the frequency of adverse events in previously tested safe dosages of pridopidine. The adverse events include, but are not limited to, QT interval prolongation, gastrointestinal disorders, and psychiatric disorders. The problem to be solved by this application is to provide new formulations of high dose pridopidine which reduce the frequency of the adverse events. By preventing the C_max from reaching very high values, applicants can limit the adverse events, such as those shown in Example 1. It was not known that one should prevent the C_max of pridopidine from peaking in order to minimize some or all adverse events related to a pridopidine dose. With the understanding of the problem, applicants invented the present invention, a modified release dosage form of pridopidine which prevents the C_max from rising above previously tested safe doses.

Example 2: Pridopidine dosage forms.

Dosage forms comprising 90mg Pridopidine were formulated and the in vitro dissolution rate was tested.
Dosage forms comprising 101.6mg Pridopidine HCl (equivalent to 90mg Pridopidine base) were formulated by matrix mechanism using excipients in combination with several hydrophilic (water-soluble) and/or hydrophobic (water-insoluble) carriers.
A hydrophilic matrix, modified release system is a dynamic one involving polymer wetting, polymer hydration, gel formation, swelling and polymer dissolution. The rate of the drug release is determined by diffusion (if soluble) through the gel and by the rate of tablet erosion. At the same time, other soluble excipients or drugs will also wet, dissolve and diffuse out of the matrix while insoluble materials will be held in place until the surrounding polymer/excipient/drug complex erodes or dissolves away.

Manufacture of Modified Release (MR) Pridopidine dosage forms

A matrix tablet was prepared by wet granulation method. A granule was prepared to be used in combination with carrier or carriers and selected excipients for obtaining modified release formulations.

Manufacture of pridopidine granulates:

High Shear Granulation: All granulation ingredients were added to the granulator bowl and pre-blend (chopper at medium/high speed; impeller at medium/low speed) for a sufficient time to ensure mixture uniformity and to break-up any agglomerates. Granulations liquid was added and blend (chopper at high speed; impeller at medium speed). The quantity of granulation fluid required is highly formulation dependent. The granules were dried using a fluid bed dryer and milled by Quadro Comill.

Granules of 90mg and high dose pridopidine are presented in Table 3.1, Table 3.2, and Table 3.3, respectively.

Table 3.1: Composition of Granules R1-R3

Batch No.	Use	R1	R2	R3
Composition	-	mg/tab	mg/tab	mg/tab
Pridopidine HCl	Drug Substance	101.6	101.6	101.6
Ethylcellulose (Ethocel^™ 7 Premium)	Binder	20.4	20.4	50.8
CaHPO₄	Insoluble filler	-	178.0	101.6
Pregelatinized Starch (Starch 1500^®)	Filler, disintegrant, binder	-	-	50.8
Total Weight	-	122.0	300.0	304.8

Table 3.2: Composition of Granules R4 based on HD IR Capsules formulation

Batch No.	Use	R4
Composition	-	mg/Tab
Pridopidine HCl	Drug Substance	127.0
Microcrystalline Cellulose (Avicel PH 102)	Diluent/ disintegrant	65.0
Hydroxypropyl Cellulose (Klucel)	Binder	10.0
Total Weight	-	202.0

Table 3.3: Composition of Granules R5

Batch No.	Use	R5
Composition	-	mg/Tab
Pridopidine HCl	Drug Substance	101.6
Silicified Microcrystalline Cellulose (Prosolv^® SMCC 90)	Filler	63.2

Dissolution test of the dosage forms:

A typical dissolution for Pridopidine tablets uses an USP #1 apparatus (basket), rotating at 100 RPM and 37°C in 500mL of HCl 0.1N for 2 hours and then in buffer phosphate pH 6.8, for 12 hours. The buffer phosphate is prepared by dissolving 6.805 g of KH2PO4 phosphate dibasic and 4.48mL 5M NaOH, diluted to 1000mL with deionized water and mixed thoroughly. The sample is tested by UV detector set at 268 nm and then returned to the dissolution vessel. The same dissolution results were obtained using an USP #2 apparatus (paddle) at 75 RPM.

Example 3: Modified Release (MR) Pridopidine dosage forms of the invention.

Dosage forms were formed with the R5 granulate and are included within the invention.

Dosage forms included within the invention are presented in Table 4.

Table 4: Dosage Forms included in the present invention

Formulation Ingredients	Composition (mg)/Prototype No.
	MR-1	MR-2	MR-3
Pridopidine HCl	101.6	101.6	101.6
Silicified Microcrystalline Cellulose (Prosolv^® SMCC 90)	63.2	63.2	63.2
Hydroxypropyl methylcellulose (Methocel ^™ K100M Premium CR)	^∗∗	150.0	150.0
Hydrogenated Castor Oil (HCO)	150.0	^∗∗	^∗∗
Lactose SD	70.0	70.0	70.0
Colloidal Silicon Dioxide (Aerosil^®)	7.2	7.2	7.2
Magnesium Stearate	8.0	8.0	8.0
Ethylcellulose (Surelease^®)	^∗∗	^∗∗	6.0-12.0
Total	400.0±5%^∗	400.0±5%	406.0-412.0±5%

The in vitro dissolution results are presented in Table 5 and Figure 3.

Table 5: In vitro dissolution profile of dosage forms MR-1, MR-2, and MR-3

Sampling time (min)	pH	% dissolved
Sampling time (min)	pH	MR-1	MR-2	MR-3 (8mg Ethylcellulose/tablet)
60	1.2	41	35	9
120	1.2	57	54	24
180	6.8	68	67	37
240	6.8	75	76	48
360	6.8	86	88	64
480	6.8	92	96	77
600	6.8	97	101	86
720	6.8			94

In addition to the dissolution profiles of formulations determined shortly after formation (T0), dissolution profiles of formulations MR-1, MR-2 and MR-3 were also determined after 3 months (3M) and 4 month (4M), as presented in Table 5A. In addition, the dissolution profiles of different batches were determined, and are also presented in Table 5A. For each formulation, Batch 1 is the same batch presented in Table 5.

Table 5A: Dissolution profile of different batches of formulations MR-1, MR-2 and MR-3

MR-1
Time	Time	Batch 1			Batch 2	Batch 3	Batch 4
hours	min	T0	3M	4M	T0	T0	T0
1	60	41	33	34	36	35	34
2	120	57	46	49	50	49	47
3	180	68	60	65	60	58	56
4	240	75	67	72	68	65	63
6	360	86	77	82	79	75	73
8	480	92	84	89	87	83	81
10	600	97	89	95	92	89	87
12	720	100	92	99	96	93	92
14	840	102	95	101	99	96	96

MR-2
Time	Time	Batch 1			Batch 2	Batch 3	Batch 4
hours	min	T0	3M	4M	T0	T0	T0
1	60	36	31	31	36	28
2	120	54	46	46	53	42	28
3	180	67	61	62	66	55	42
4	240	76	69	72	76	65	54
6	360	88	81	87	89	78	63
8	480	96	88	92	97	88	75
10	600	101	93	97	103	94	83
12	720	104	96	100	107	98	88
14	840	106	98	102	109	100	92

MR-3
Time	Time	Batch 1ⁱ	Batch 2ⁱⁱ	Batch 3ⁱⁱⁱ
hours	min	T0	T0	T0	3M
1	60	9	5	6	16
2	120	24	15	18	30
3	180	37	26	31	45
4	240	48	35	42	55
6	360	64	50	58	71
8	480	77	63	72	-
10	600	87	73	-	90
12	720	94	82	90	97
14	840	100	89	-	-

^i. 8mg Ethylcellulose/tablet
^ii. 10mg Ethylcellulose/tablet
^iii. 7mg Ethylcellulose/tablet

Example 4: Immediate Release (IR) Pridopidine dosage forms

In comparison to the MR Pridopidine dosage forms, the IR dosage forms of Pridopidine were almost totally dissolved after about 20-30 minutes. Exemplary dissolution profiles of IR dosage forms of Pridopidine are presented in Table 5.1. The composition of the IR dosages forms in Table 5.1 are presented in Table 5.2:

Table 5.2: Composition of IR Dosage Forms

	Batch No.	AA	DD
Formulation	Use	Composition mg/capsule
Pridopidine HCl	Drug Substance	25.4	50.8
Silicified Microcrystalline Cellulose (Prosolv^® SMCC 90)	Filler	43.2	86.4
Magnesium Stearate	Lubricant	1.4	2.8

Additional formulations developed during the development of the formulations of the present invention are presented in Table 5.3. As can be seen, formulation A was formulated without a carrier. Some formulations, such as formulation B, C and D, included rate controlling excipients (Table 5.3).
The dissolution profiles of formulations A, B, C and D are presented in Table 5.4. As shown in Table 5.4, formulation A provides immediate release of drug substance (1 hour).
The presence of up to 16% of hydrophobic carrier Hydrogenated Castor Oil (HCO) in matrix tablets with (formulation B) or without (formulation C) soluble filler (Lactose), did not result in delayed release of Pridopidine, which was released after approximately 1 hour in both cases.

Dissolution results of formulation D showed that 10% hydrophobic carrier (HCO) in formulation D also provided 1 hour release of Pridopidine.

Table 5.3 Formulations with different carriers and carrier amounts

Batch No.	Use	A	B	c	D
Composition	-	mg/Tablet	mg/Tablet	mg/Tablet	mg/Tablet
Granules ¹	-	R2 300.0	R3 304.8	R3 304.8	R4 202.0
Hydroxypropyl methylcellulose (Methocel ^™ K100M Premium CR)	Hydrophilic carrier	*	*	*	*
Hydrogenated Castor Oil (HCO)	Hydrophobic carrier	*	60.0	60.0	23.0
Lactose (Anhydrous)	Soluble filler	*	75.2	*	*
Microcrystalline Cellulose and Glyceryl Monostearate (Lubritose^™ Blue)	Soluble filler	*	*	*	*
Colloidal Silicon Dioxide (Aerosil)	Flow agent or glidant	5.0	5.0	5.0	1.0
Magnesium Stearate	Lubricant	5.0	5.0	5.2	2.5
Tablet Weight		310.0	450.0	375.0	228.5
Dissolution profile²		1h release	1h release	1h release	1h release

¹ Granules R2, R3, and R4 are listed in Table 3.1, or 3.2.
² Dissolution testing was performed using USP, apparatus I at 100rpm, in 900mL purified water at 37°C.

Table 5.4 Dissolution Profiles of the Formulations in Table 5.3

	Time / Batch No.	5min	1h	3h	6h	9h	12h
Release rate (%)	A	23	101	109
	B	18	97
	C	18	106
	D	22	88	100

Summary of Examples 2-4

The exemplified dosage forms presented in Example 3 (Table 5) showed an in vitro dissolution profile wherein about 41% (MR-1), about 36% (MR-2) and as low as about 9% (MR-3) were dissolved in the first hour. After 4 hours, about 75% (MR-1), about 76% (MR-2), and about 48% (MR-3) of the Pridopidine were dissolved. Even after ten hours, not all the Pridopidine in the dosage form MR-1 was dissolved, and only 86% of the Pridopidine included in dosage form MR-3 was dissolved, in comparison to IR dosage forms of Pridopidine shown in Example 4, where more than 20% of pridopidine was already dissolved after 5 minutes, and were almost totally dissolved after about 20-60 minutes. As shown in Example 4, some formulations containing rate controlling excipients were found not to act as modified release formulation.

Example 5: Development of a pharmacokinetic model useful for the simulation of PK profile following Pridopidine administration.

PK plasma profiles resulting from administration of the dosage forms were calculated using a simulation program. The PKPlus^™module portion of Gastroplus^™ simulator software available from Simulations Plus, Incorporated, was first used to determine the best type of ACAT (Advanced Compartmental Absorption and Transit) model for immediate release pridopidine dosing.
Concentration data obtained following administration of an immediate release of pridopidine (IR) were used as an approximation for IV. The IR data was obtained from the study published by Helldén et al. (2012). Pridopidine was dosed as either 25.4mg pridopidine HCl (22.5mg pridopidine base) or 50.8 mg pridopidine (45mg pridopidine base) of an IR capsule to poor metabolizers (PM) and extensive metabolizers (EM), respectively. PK samples were taken over 50 hours post-dose. Mean plasma concentration vs. time data for the PM group after single dose were extracted using summary graphs from UN-SCAN-ITTM graph digitizing software available from Silk Scientific Inc. Plasma concentration for the following time points was inputted into the PK Plus module in hours: 0.0, 0.9, 2, 3, 4, 6, 9, 10.6, 19.7, 25, 33, and 50 hours. The PK Plus module portion estimated mean pharmacokinetic parameters and performed calculations for the goodness of fit and Akaike Information Criterion for Noncompartment, One-Compartment, Two-Compartment and Three-Compartment Models. Based on the lowest Akaike information criterion value, the two compartment model was selected as having the best fit. The model was validated by comparison to data from another Pridopidine study (Linskov 2013, Hellden 2012) as presented in Figures 4 and 5.
The model can simulate plasma concentration of poor metabolizers (PM) of Pridopidine administered with a single dose as well as multiple doses (steady state). Importantly, it has been shown that during multiple dose administration pridopidine can inhibit its own CYP2D6-driven metabolism in EM subjects, meaning that upon repeated dosing, PMs and EMs exhibit comparable exposure due to a reduction in CYP2D6-related pridopidine metabolism in EMs over time (Lindskov 2012). In relation to presented model, this means that while simulation of plasma concentrations following single dose administrations would be relevant to PMs only, results of the steady state PM can be applied to the steady state in EMs, and therefore a general population including both EMs and PMs. For the same reasons, the model is expected to fit the UM and IM phenotypes as well.

Example 6: Predicted PK parameters following administration of the oral dosage forms.

Using the dissolution profiles of the dosage forms described in Examples 2-4, and the pharmacokinetic model described in Example 5, the predicted plasma concentrations resulting from multiple administrations of MR dosage forms of pridopidine were calculated. Pharmacokinetic parameters were calculated for twice daily (b.i.d.) administration of IR formulations containing different doses of Pridopidine (with a 6.5h interval and a 7h interval between doses), and once daily administration of modified release dosage forms MR-1, MR-2, and MR-3 containing different doses of Pridopidine, both after single dose administration and at steady state. Data from 45 to 157.5 mg IR administered b.i.d. or MR dosage forms (90 to 315mg) administered once daily are presented in Table 6 (day 1) and Table 7 (steady state). The simulation calculated a PK value equivalent to mean C_max.

Table 6: Observed and Simulated Pridopidine PK parameters on day 1 following a single dose of IR dosage forms b.i.d or MR dosage forms QD

Sample Name	AUC day1 0-38h ^∗ ng/mL^∗h	Cmax ^∗ (ng/mL)	AUC day1 0-50h ^∗ ng/mL^∗h
Observed IR 45mg BID (6.5 hr between morning and afternoon dose)	9556	476
Simulated IR 45mg BID (6.5 hr between morning and afternoon dose)	9178	417	10323
Simulated IR 45mg BID (7 hr between morning and afternoon dose)	9092	414	10301
Simulated IR 67.5mg BID (7 hr between morning and afternoon dose)		611	15057
Simulated IR 90mg BID (7 hr between morning and afternoon dose)		818	20166
Simulated IR 112.5mg BID (7 hr between morning and afternoon dose)		1025	25280
Simulated IR 157.5mg BID (6.5 hr between morning and afternoon dose)		1450	41635
MR-2 (once daily, 90mg)	6780	258	7714
MR-3 (once daily, 90mg)	4809	155	5647
MR-1 (once daily, 90mg)	6890	269	7825
MR-2 (once daily, 125mg)		352	10427
MR-3 (once daily, 125mg)		209	7587
MR-1 (once daily, 125mg)		367	10583
MR-2 (once daily, 135mg)		381	11276
MR-3 (once daily, 135mg)		227	8207
MR-1 (once daily, 135mg)		397	11445
MR-2 (once daily, 150mg)		424	12551
MR-3 (once daily, 150mg)		252	9138
MR-1 (once daily, 150mg)		442	12737
MR-2 (once daily, 180mg)		510	15101
MR-3 (once daily, 180mg)		304	11001
MR-1 (once daily, 180mg)		531	15325
MR-2 (once daily, 200mg)		567	16802
MR-3 (once daily, 200mg)		338	12244
MR-1 (once daily, 200mg)		591	17050
MR-2 (once daily, 225mg)		639	18929
MR-1 (once daily, 225mg)		381	13864
MR-3 (once daily, 225mg)		666	19208
MR-2 (once daily, 250mg)		711	21057
MR-3 (once daily, 250mg)		424	15427
MR-1 (once daily, 250mg)		740	21367
MR-2 (once daily, 315mg)		897	26593
MR-3 (once daily, 315mg)		536	19493
MR-1 (once daily, 315mg)		934	26879

^∗ AUC_0-38 and AUC_0-50 can be considered a good estimation of AUC_inf

Table 7: Pridopidine Pharmacokinetic (PK) parameters following multiple daily doses of pridopidine (IR dosage form bid or MR dosage form QD), at steady state

Dose and Regimen	Mean
Dose and Regimen	^∗AUCtau,ss (hr^∗ng/mL)	Cmax,ss (ng/mL)
Observed IR 45mg BID (6.5 hr between morning and afternoon dose)	12547	807
Simulated IR 45mg BID (6.5 hr between morning and afternoon dose)	12634	675
Simulated IR 45mg BID (7 hr between morning and afternoon dose)	12641	670
Simulated IR 67.5mg BID (6.5 hr between morning and afternoon dose)	18951	1013
Simulated IR 90mg BID (6.5 hr between morning and afternoon dose)	25270	1351
Simulated IR 112.5mg BID (6.5 hr between morning and afternoon dose)	31585	1689
Simulated IR 157.5mg BID (6.5 hr between morning and afternoon dose)	43547	2336
MR-2 (once daily, 90mg)	9479	495
MR-3 (once daily, 90mg)	7236	340
MR-1 (once daily, 90mg)	9591	508
MR-2 (once daily, 100mg)	10532	550
MR-3 (once daily, 100mg)	8052	378
MR-1 (once daily, 100mg)	10657	564
MR-2 (once daily, 125mg)	13165	688
MR-3 (once daily, 125mg)	10051	472
MR-1 (once daily, 125mg)	13322	706
MR-2 (once daily, 135mg)	14218	743
MR-3 (once daily, 135mg)	10855	510
MR-1 (once daily, 135mg)	14387	762
MR-2 (once daily, 150mg)	15798	826
MR-3 (once daily, 150mg)	12061	567
MR-1 (once daily, 150mg)	15986	847
MR-2 (once daily, 180mg)	18957	991.1
MR-3 (once daily, 180mg)	14474	680
MR-1 (once daily, 180mg)	19183	1016
MR-2 (once daily, 225mg)	23698	1239
MR-1 (once daily, 225mg)	23981	1271
MR-2 (once daily, 315mg)	32431	1712
MR-3 (once daily, 315mg)	28068	1169
MR-1 (once daily, 315mg)	32824	1757

^∗ dosing interval (tau) = 24 hours.

Dissolution data presented for the 90 mg dosage forms were experimentally tested as described in Examples 2-4. The dissolution data presented for dosage forms higher than 90 mg are presented based on a simulation which used the profiles of 90mg samples.

Results and discussion of Examples 5-6:

Safety issues such as gastrointestinal disorders, psychiatric disorders, and cardiac adverse events are dose-dependent. Particularly for QT, these safety concerns are linked to maximum drug concentrations (Cmax) rather than to AUC. However, it is not known if C_max or AUC are responsible for other adverse events such as CNS related and GI related adverse events.
The dosage forms of the present invention were shown to provide reduced maximal blood concentration (C_max) compared to b.i.d. adminitration of the same dose of drug per day, while maintaining AUC similar to those in previous studies (Huntington Study Group HART Investigators 2013, Yebenes 2011).
The calculated C_max resulting from the administration of 90mg Pridopidine in a MR dosage form of the present invention was found to be lower compared to C_max resulting from the 45mg IR admimistered b.i.d (Table 7), presenting a better safety profile. In addition the calculated AUCtau,ss for the 90mg MR administration was comparable to AUC tau,ss found in subjects administered with 45mg IR b.i.d in the MAD study. Similarly, the calculated C_max resulting from the administration of 135mg Pridopidine in a MR dosage form was lower compared to C_max resulting from the 67.5mg IR admimistered b.i.d; the calculated C_max resulting from the administration of 180mg Pridopidine in a MR dosage form was lower compared to C_max resulting from the 90mg IR admimistered b.i.d; the calculated C_max resulting from the administration of 225mg Pridopidine in a MR dosage form was lower compared to C_max resulting from the 112.5mg IR admimistered b.i.d, and the calculated C_max resulting from the administration of 315 Pridopidine in a MR dosage form was lower compared to C_max resulting from the 157.5mg IR admimistered b.i.d (Table 7). The AUCtau,ss of these doses is higher than the AUCtau,ss related to 45mg IR b.i.d. The AUCtau,ss of these doses would be appreciated by the person skilled in the art to be relevant to therapeutically effective amounts of the formulation.
In addition, the calculated C_max,ss resulting from administration of MR dosage forms comprising 100mg and 125mg Pridopidine, was lower than the C_max resulting from 45mg IR admimistered b.i.d (a total dose of 90mg per day;see Table 7). For the 100mg MR dosage form, calculated AUCtau,ss was about 80% of the 45mg IR b.i.d., and the AUCtau,ss calculated for the 125mg MR dosage form was similar to 45mg IR b.i.d. Importantly, both were higher than mean AUCtau,ss resulting from 45mg IR b.i.d. administration in the MAD study. These findings show that even for MR dosage forms comprising more than the same dose per day administed b.i.d., the safety profile was improved, while clinical activity maintained.

Example 7

Three dosage forms of pridopidine are prepared according to Examples 2 and 3, MR-1, MR-2 and MR-3. Periodic oral administration of MR-1, MR-2 or MR-3 to a human patient afflicted with Huntington's Disease shows that the frequency of adverse events decreases compared to the frequence of adverse events in Example 1.

Example 8

Three dosage forms of pridopidine are prepared according to Examples 2-3, MR-1, MR-2 and MR-3, however the amount of pridopidine is 100 mg (113 mg pridopidine HCl) and each of the other components of MR-1, MR-2 and MR-3 are increased proportionally. Periodic oral administration of the dose forms to a human patient afflicted with Hungington's Disease shows that the C_max is equal to or less than previously tested safe doses.

Example 9

Three dosage forms of pridopidine are prepared according to Examples 2-3, MR-1, MR-2 and MR-3, however the amount of pridopidine is 125 mg (141 mg pridopidine HCl) and each of the other components of MR-1, MR-2 and MR-3 are increased proportionally. Periodic oral administration of the dose forms to a human patient afflicted with Huntington's Disease shows that the C_max is equal to or less than previously tested safe doses.

Example 10

Three dosage forms of pridopidine are prepared according to Examples 2-3, MR-1, MR-2 and MR-3, however the amount of pridopidine is 135 mg (153 mg pridopidine HCl) and each of the other components of MR-1, MR-2 and MR-3 are increased proportionally. Periodic oral administration of the dose forms to a human patient afflicted with Huntington's Disease shows that the C_max is equal to or less than previously tested safe doses.

Example 11

Three dosage forms of pridopidine are prepared according to Examples 2-3, MR-1, MR-2 and MR-3, however the amount of pridopidine is 150 mg (170 mg pridopidine HCl) and each of the other components of MR-1, MR-2 and MR-3 are increased proportionally. Periodic oral administration of the dose forms to a human patient afflicted with Huntington's Disease shows that the C_max is equal to or less than previously tested safe doses.

Example 12

Three dosage forms of pridopidine are prepared according to Examples 2-3, MR-1, MR-2 and MR-3, however the amount of pridopidine is 180 mg (203 mg pridopidine HCl) and each of the other components of MR-1, MR-2 and MR-3 are increased proportionally. Periodic oral administration of the dose forms to a human patient afflicted with Huntington's Disease shows that the C_max is equal to or less than previously tested safe doses.

Example 13

Three dosage forms of pridopidine are prepared according to Examples 2-3, MR-1, MR-2 and MR-3, however the amount of pridopidine is 225 mg (254 mg pridopidine HCl) and each of the other components of MR-1, MR-2 and MR-3 are increased proportionally. Periodic oral administration of the dose forms to a human patient afflicted with Huntington's Disease shows that the C_max is equal to or less than previously tested safe doses.
To summarize, the inventors of the present invention managed to fomulate therapeutically effective dosage forms with an increased safety profile compared to b.i.d. administration of the same dose per day or less.
Additionally, treatments of acute and chronic neurological and neuropsychiatric diseases, such as Huntington's disease, have the problem of treatment compliance because the patient or caretaker may forget to administer the medication. Accordingly, the oral dosage forms of the present invention provide advantages over the formerly known (b.i.d.) oral dosages. The oral dosage forms of the present invention are adapted for administration once daily, providing reduced pill burden for patients who resist treatment, increasing convenience for patients and caregivers and leading to greater compliance and less burden on family members.

Example 14: PK study in Beagle dogs following single dose administration of the MR-1, MR-2 and MR-3 formulations.

The pharmacokinetics of pridopidine in male Beagle dogs was tested following oral administration of an immediate release (IR) formulation and three modified release (MR) formulations. The dogs were divided to 4 groups: Group 1 received one administration of formulation MR-1, Group 2 received one administration of formulation MR-2 and Group 3 received one administration of formulation MR-3. Each formulation comprised 90mg of Pridopidine. Pridopidine plasma concentration was measured at several time-points at 0.5-36 hours after administration.
Group 4 received 45 mg Pridopidine in IR formulation twice with 3h interval. Pridopidine plasma concentration was measured at several time-points at 0.5-36 hours after first administration.
The study was done under fasting condition starting 12 h before administration, and lasting additional 7h post first administration.
The results are presented in Table 8.

Example 15: additional analysis of PK parameters.

The concentration of Pridopidine in the plasma samples in Example 14 was determined using liquid chromatography-tandem mass spectrometry LC-MS/MS. In an additional analysis, samples containing higher concentration of an analyte than the upper limit of the quantification (ULOQ: 2000 ng/ml pridopidine) was re-analyzed after 10 times dilution.
Briefly, the blood samples were centrifuged (within maximum 60 minutes after collection) at 2500 g at 5°C for 15 minutes. The frozen plasma samples were stored in an ultra-freezer ( -70±10°C). In the plasma samples the concentration of pridopidine were determined liquid chromatography-tandem mass spectrometry LC-MS/MS. As described, the samples containing higher concentration of an analyte than the upper limit of the quantification (ULOQ: 2000 ng/ml pridopidine) were re-analyzed after 10 times dilution .
For each formulation from the individual data the mean and S.D. values were calculated for each time-point generating a mean plasma concentrations versus time curve.
The pharmacokinetic analysis was performed using validated Phoenix WinNonlin Version 6.3 software (Pharsight Corporation, USA). The individual and mean pharmacokinetic parameters were calculated using a non-compartmental method.

Results:

Figure 6 shows the mean plasma level curves (with S.D.) of pridopidine (6a-b) for formulations MR-1, MR-2, and MR-3. Two administrations of the immediate release (IR) formulation administered 3h apart resulted in an initial peak concentration followed by an initial decline then a second peak followed by the terminal elimination phase. In comparison, The MR formulation had a prolonged absorption from the MR formulations that resulted in a maximum concentration followed by a terminal elimination phase.

For all formulations the AUC_(0-inf) and C_max values were normalized to the nominal 12 mg/kg pridopidine dose. The T_max,dose normalized C_max and dose normalized total exposures (AUC_(0-inf),norm values) are summarized in Table 9.

Table 9

	Group
	1 (MR-1) (S.D)	2 (MR-2) (S.D)	3 (MR-3) (S.D)	4 (IR) (1st dose) (S.D)	4 (IR) (2 ^nd dose) (S.D)
C_max,norm [ng/ml]	1110 (200)	1170 (235)	803 (228)	1550 (313)	2030 (538)
T_max pridopidine	1.94 (0.904)	2.38 (1.03)	3.63 (1.62)	1.16 (0.351)	3.91 (1.14)
AUC_(0-inf),norm [h^∗ng/ml]	6340 (1610)	7010 (3520)	6080 (2830)		9410 (3380)

As can be seen, formulations MR-1 and MR-2 showed similar kinetic profiles while the most delayed absorption was observed for formulation MR-3. IR formulation resulted in the first pridopidine peak within the shortest period post-dose: at approximately 1 hour. For MR formulations the pridopidine peaks occurred later: at approximately 2 hours for formulation MR-1, 2.5 hours for formulation MR-2 and 3.5 hours for formulation MR-3.
The relative peak levels of the MR formulations compared to the higher, second peak level of the reference IR formulation (F_rel_C_max), and the relative total exposure (F_rel AUC_inf) were calculated from the total group means (Table 10). Table 10

1 (MR-1) 2 (MR-2) 3 (MR-3)

F_rel C_max 0.547 0.576 0.396

Mean F_rel AUC_inf 0.721 0.746 0.625
The results show that C_max resulting from the once daily administration of 90 mg Pridopidine in formulations MR-1, MR-2 and MR-3, was 55%, 58% and 40%, respectively, of the C_max resulting from 45 mg Pridopidine in IR formulation given bid. AUC_inf resulting from the single once daily administration of 90 mg Pridopidine in formulations MR-1, MR-2 and MR-3 was 72%, 75% and 63%, respectively of AUC_inf resulting from bid administration of 45 mg Pridopidine in the IR formulation.

Example 16

Tablet dosage forms of pridopidine were prepared with granulates R1-R4 (Tables 3.1 or 3.2) and are presented in Table 11. The dissolution profile of these dosage forms are also listed in Table 11. Dissolution testing was performed using USP apparatus I at 100rpm, in 900mL purified water at 37°C. The detailed dissolution profiles of the dosage forms listed in Table 11 are shown in Table 12.

It would be appreciated by the person skilled in the art that the Dosage Forms presented in Table 11 have a modified release dosage form dissolution profile.

Table 11

No.	Use	MR-4	MR-5	MR-6	MR-7	MR-8	MR-9	MR-10	MR-11
Composition	-	mg/Tab	mg/Tab	mg/Tab	mg/Tab	mg/Tab	mg/Tab	mg/Tab	mg/Tab
Granules ¹	-	R1 122.0	R4 163.2	R3 304.8	R3 304.8	R1 122.0	R1 122.0	R2 300.0	R4 163.2
Calcium Phosphate Dibasic	Insoluble filler	*	*	*	*	154.0	*	*	*
Hydroxypropyl Methyl Cellulose (HPMC) Methocel K100 PR CR	Hydrophilic carrier	122.0	*	90.0	90.0	120.0	120.0	90.0	150.0
(HPMC) Methocel K15M CR	Hydrophilic carrier	*	*	*	*	*	*	*	25.0
Hydrogenated Castor Oil	Hydrophobic carrier	30.0	175.0	*	60.0	*	*	*	*
Aerosil	Flow agent	*	*	5.0	5.0	2.0	2.0	5.0	*
Mg.Stearate	Lubricant	2.0	1.8	5.2	5.2	2.0	2.0	5.0	1.8
LubriTose Blue²	Lubricant	*	160.0	*	*	*	*	*	*
LubriTose Yellow	Lubricant	*	*	*	*	*	*	*	160.0
Lactose Anhydrous	Soluble filler	*	*	150.0	75.0	*	154.0	100	*
Tablet Weight		276.0	500.0	555.0	540.0	400.0	400.0	500.0	500.0
Dissolution profile³		12h release	9-10h release	9h release	9h release	9h release	9h release	9h release	9-12 release

¹ Granules R1, R2, R3, and R4 are listed in Table 3.1, or 3.2.
² Lactose + (2%-10% Glyceryl MonoStearate): yellow contain 10% GMS and blue contain 2% GMS.
³ Dissolution testing was performed using USP, apparatus I at 100rpm, in 900mL purified water at 37°C.

Table 12: Dissolution Profiles of the Formulations in Table 11

	Time / Batch	5min	1h	3h	6h	9h	12h
Release Rate (%)	MR-4	8	37	62	83	94	99
	MR-5	12	40	65	83	94	101
	MR-6	3	30	60	84	92	95
	MR-7	5	36	67	88	97	100
	MR-8	6	37	68	91	103
	MR-9	3	32	68	94	105
	MR-10	4	38	72	95	102
	MR-11	5	32	60	82	93	100

References:

Clinicaltrials.gov Clinical Trial Identifier NCT02006472, "A Phase 2, to Evaluating the Safety and Efficacy of Pridopidine Versus Placebo for Symptomatic Treatment in Patients With Huntington's Disease."
de Yebenes JG, Landwehrmeyer B, Squitieri F, Reilmann R, Rosser A, Barker RA, Saft C, Magnet MK, Sword A, Rembratt A, Tedroff J; MermaiHD study investigators, "Pridopidine for the treatment of motor function in patients with Huntington's disease (MermaiHD): a .
Huntington Study Group HART Investigators, "A randomized, double-blind, placebo-controlled trial of pridopidine in Huntington's disease," Mov Disord. 2013 Sep;28(10):1407-15. doi: 10.1002/mds.25362. Epub 2013 Feb 28.
Helldén A, Panagiotidis G, Johansson P, Waters N, Waters S, Tedroff J, Bertilsson L. "The dopaminergic stabilizer pridopidine is to a major extent N-depropylated by CYP2D6 in humans" Eur J Clin Pharmacol. 2012 Sep; 68(9):1281-6. Epub 2012 .
Lindskov Krog P, Osterberg O, Gundorf Drewes P, Rembratt Å, Schultz A, Timmer W. "Pharmacokinetic and tolerability profile of pridopidine in healthy-volunteer poor and extensive CYP2D6 metabolizers, following single and multiple dosing" Eur J Drug Metab Pharmacokinet. 2013 Mar;38(1):43-51. Epub 2012 Sep 5.
Østerberg, et al. "A single center, randomized, placebo-controlled, double-blind study to evaluate the safety, tolerability, and pharmacokinetics of multiple-ascending doses of pridopidine in healthy volunteers" Poster presented at Sixth Annual Huntington Disease Clinical Research Symposium, Nov 2012, Seattle, Washington, USA. Neurotherapeutics The following numbered embodiments define various aspects and features of the present invention and correspond to the original claims of the parent PCT application PCT/US2015/012248 (published as WO 2015/112601 ):
1. 1. A modified release solid oral dosage form comprising a therapeutically effective amount of Pridopidine or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable rate controlling excipient, wherein the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a Mean C_max of about 1,400 ng/ml or less.
2. 2. The modified release solid oral dosage form of embodiment 1, wherein the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a Mean C_max of a) about 1,157 ng/ml or less; b) about 906 ng/ml or less; or c) about 499 ng/ml or less.
3. 3. The modified release solid oral dosage form of embodiment 1, wherein the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a Mean C_max of: a) about 718 ng/ml or less measured after single dose administration; b) about 486 ng/ml or less measured after single dose administration; or c) about 327 ng/ml or less measured after single dose administration.
4. 4. The modified release solid oral dosage form of embodiment 1, wherein the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a C_max a) from about 382 ng/ml to about 1,568 ng/ml; b) between 871 ng/ml and 1,568 ng/ml; c) between 382 ng/ml and 1,287 ng/ml; or d) between 639 ng/ml and 1,287 ng/ml.
5. 5. The modified release solid oral dosage form of embodiment 1, wherein the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a C_max a) from about 244 ng/ml to about 1,002 ng/ml; b) between 244 ng/ml and 813 ng/ml; c) between 493 ng/ml and 1,002 ng/ml; or d) between 324 ng/ml and 813 ng/ml.
6. 6. The modified release solid oral dosage forms of any of embodiments 1, 2 and 4, wherein the AUC_tau is about 5,253 ng h/ml or more.
7. 7. The modified release solid oral dosage forms of any of embodiments 1, 3 and 5, wherein the AUC_0-inf is about 2,249 ng h/ml or more.
8. 8. The modified release solid oral dosage forms of any of embodiments 1, 2, 4 and 6, wherein the Mean AUC_tau is a) about 7,178 ng h/ml or more; b) about 14,185 ng h/ml or more; or c) about 18,065 ng h/ml or more.
9. 9. The modified release solid oral dosage forms of any of embodiments 1, 3, 5, and 7, wherein the Mean AUC_0-inf is about a) 5,043 ng h/ml or more; b) about 7,897 ng h/ml or more; or c) about 13,594 ng h/ml or more.
10. 10. The modified release solid oral dosage form of any one of embodiments 1-9, wherein the dosage form comprises from about 22.5mg to about 350mg, from about 45mg to about 300mg, or from about 90mg to about 250mg, Pridopidine or a pharmaceutically acceptable salt thereof.
11. 11. The modified release solid oral dosage form of any one of embodiments 1-9, wherein the dosage form comprises at least about 90mg, at least about 100mg, at least about 125mg,at least about 135mg, at least about 150mg, at least about 180mg, at least about 200mg, at least about 225mg, at least about 250mg, or at least about 315mg Pridopidine or a pharmaceutically acceptable salt thereof.
12. 12. The modified release solid oral dosage form of any one of embodiments 1-9, wherein the dosage form comprises about 90mg, about 100mg, about 125mg, about 135mg, about 150mg, about 180mg, about 200mg, about 225mg, about 250mg,or about 315mg Pridopidine or a pharmaceutically acceptable salt thereof.
13. 13. The modified release solid oral dosage form of any one of embodiments 1, 2, 4, 6, 8, and 10-12, wherein the in vivo plasma profile is measured at steady state.
14. 14. The modified release solid oral dosage form of any one of embodiments 1, 3, 5, 7, 9, and 10-12, wherein the in vivo plasma profile is measured after single dose administration.
15. 15. The modified release solid oral dosage form of embodiment 14 wherein AUC_inf is estimated from AUC_0-24.
16. 16. A modified release solid oral dosage form comprising a therapeutically effective amount of Pridopidine or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable rate controlling excipient, and wherein the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a Mean C_max which is lower than a Mean C_max resulting from the b.i.d. administration of an immediate release solid oral dosage form which contains:
  1. a) half the amount of the Pridopidine or a pharmaceutically acceptable salt thereof or
  2. b) between 10% and 49% of the amount of the Pridopidine or a pharmaceutically acceptable salt thereof.
17. 17. The modified release solid oral dosage form of embodiment 16, wherein a) the amount of Pridopidine or a pharmaceutically acceptable salt thereof is more than 45 mg of Pridopidine; b) the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 90 mg of Pridopidine and the immediate release dosage form contains about 45 mg of Pridopidine; c) the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 100 mg of Pridopidine and the immediate release solid oral dosage form contains about 45 mg of Pridopidine; d) the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 125 mg of Pridopidine and the immediate release solid oral dosage form contains about 45 mg of Pridopidine; e) the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 135 mg of Pridopidine and the immediate release solid oral dosage form contains about 45 mg of Pridopidine; f) the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 135 mg of Pridopidine and the immediate release solid oral dosage form contains about 67.5 mg of Pridopidine; g) the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 150 mg of Pridopidine and the immediate release solid oral dosage form contains about 45 mg of Pridopidine; h) the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 150 mg of Pridopidine and the immediate release solid oral dosage form contains about 67.5 mg of Pridopidine; i) the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 180 mg of Pridopidine and the immediate release solid oral dosage form contains about 45 mg of Pridopidine; j) the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 180 mg of Pridopidine and the immediate release solid oral dosage form contains about 67.5 mg of Pridopidine; k) the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 180 mg of Pridopidine and the immediate release solid oral dosage form contains about 90 mg of Pridopidine; 1) the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 200 mg of Pridopidine and the immediate release solid oral dosage form contains about 45 mg of Pridopidine; m) the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 200 mg of Pridopidine and the immediate release solid oral dosage form contains about 67.5 mg of Pridopidine; n) the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 200 mg of Pridopidine and the immediate release solid oral dosage form contains about 90 mg of Pridopidine; o) the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 225 mg of Pridopidine and the immediate release solid oral dosage form contains about 45 mg of Pridopidine; p) the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 225 mg of Pridopidine and the immediate release solid oral dosage form contains about 67.5 mg of Pridopidine; q) the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 225 mg of Pridopidine and the immediate release solid oral dosage form contains about 90 mg of Pridopidine; r) the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 225 mg of Pridopidine and the immediate release solid oral dosage form contains about 112.5 mg of Pridopidine; s) the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 250 mg of Pridopidine and the immediate release solid oral dosage form contains about 45 mg of Pridopidine; t) the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 250 mg of Pridopidine and the immediate release solid oral dosage form contains about 67.5 mg of Pridopidine; u) the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 250 mg of Pridopidine and the immediate release solid oral dosage form contains about 90 mg of Pridopidine; v) the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 250 mg of Pridopidine and the immediate release solid oral dosage form contains about 112.5 mg of Pridopidine; w) the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 315 mg of Pridopidine and the immediate release solid oral dosage form contains about 45 mg of Pridopidine; x) the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 315 mg of Pridopidine and the immediate release solid oral dosage form contains about 67.5 mg of Pridopidine; y) the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 315 mg of Pridopidine and the immediate release solid oral dosage form contains about 90 mg of Pridopidine; z) the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 315 mg of Pridopidine and the immediate release solid oral dosage form contains about 112.5 mg of Pridopidine; or aa) the amount of Pridopidine or a pharmaceutically acceptable salt thereof is at least about 315 mg of Pridopidine and the immediate release solid oral dosage form contains about 157.5 mg of Pridopidine.
18. 18. The modified release solid oral dosage form of embodiment 16, wherein the amount of Pridopidine or a pharmaceutically acceptable salt thereof is about 90 mg, about 100 mg, about 125 mg, about 135 mg, about 150 mg, about 180 mg, about 200 mg, about 225 mg, about 250 mg, or about 315 mg,
19. 19. The modified release solid oral dosage form of any one of embodiments 16-18, wherein
  1. a) the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a Mean AUC_tau which is at least about 50% of the Mean AUC_tau provided by the b.i.d. administration of an immediate release solid oral dosage form which contains half the amount of the Pridopidine or a pharmaceutically acceptable salt thereof;
  2. b) the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a Mean AUC_tau which is at least about 60% of the Mean AUC_tau provided by the b.i.d. administration of an immediate release solid oral dosage form which contains half the amount of the Pridopidine or a pharmaceutically acceptable salt thereof;
  3. c) the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a Mean AUC_tau which is at least about 70% of the Mean AUC_tau provided by the b.i.d. administration of an immediate release solid oral dosage form which contains half the amount of the Pridopidine or a pharmaceutically acceptable salt thereof;
  4. d) the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a Mean AUC_tau which is at least about 80% of the Mean AUC_tau provided by the b.i.d. administration of an immediate release solid oral dosage form which contains half the amount of the Pridopidine or a pharmaceutically acceptable salt thereof;
  5. e) the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a Mean AUC_tau which is at least about 90% of the Mean AUC_tau provided by the b.i.d. administration of an immediate release solid oral dosage form which contains half the amount of the Pridopidine or a pharmaceutically acceptable salt thereof; or f) the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a Mean AUC_tau which is at least about 95% of the Mean AUC_tau provided by the b.i.d. administration of an immediate release solid oral dosage form which contains half the amount of the Pridopidine or a pharmaceutically acceptable salt thereof.
20. 20. The modified release solid oral dosage form of any one of embodiments 16-19, wherein the b.i.d. administration of an immediate release solid oral dosage form has a time interval between doses of 5-10 hours, 6-8 hours, 6.5 hours, or 7 hours.
21. 21. The modified release solid oral dosage form of any one of embodiments 1-20, wherein the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a Mean C_max which is reduced by a percentage compared to the Mean C_max resulting from the b.i.d. administration of an immediate release dosage form which contains half the amount of the Pridopidine or a pharmaceutically acceptable salt thereof wherein the percentage is at least 5%.
22. 22. The modified release solid oral dosage form of embodiment 21, wherein the percentage is a) at least 10%; b) at least 20%; c) at least 30%; d) at least 40%; e) at least 50%; f) at least 60%; g) at least 70%; h) between 10% and 60%; i) between 20% and 50%; j) about 25%; k)about 35%; or 1) about 50%.
23. 23. The modified release solid oral dosage form of any one of embodiments 1-22, wherein the mean time required to reach the maximal plasma, serum or blood concentration of the drug, following administration of the drug is more than 2 hours or more than 4 hours.
24. 24. The modified release solid oral dosage form according to any one of embodiments 1-23, wherein the pharmaceutically acceptable salt of Pridopidine is hydrochloride salt.
25. 25. The modified release solid oral dosage form of any one of embodiments 16-24, wherein the in vivo plasma profile is measured at steady state.
26. 26. The modified release solid oral dosage form of any one of embodiments 16-18 and 20-24, wherein the in vivo plasma profile is measured after single dose administration.
27. 27. The modified release solid oral dosage form of embodiment 26 wherein a) the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a mean AUC_0-inf which is at least about 50% of the mean AUC_0-inf provided by the b.i.d. administration of an immediate release solid oral dosage form which contains half the amount of the Pridopidine or a pharmaceutically acceptable salt thereof; b) the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a mean AUC_0-inf which is at least about 55% of the mean AUC_0-inf provided by the b.i.d. administration of an immediate release solid oral dosage form which contains half the amount of the Pridopidine or a pharmaceutically acceptable salt thereof; or c) the solid oral dosage form provides an in vivo plasma pridopidine concentration profile having a mean AUC_0-inf which is at least about 75% of the mean AUC_0-inf provided by the b.i.d. administration of an immediate release solid oral dosage form which contains half the amount of the Pridopidine or a pharmaceutically acceptable salt thereof.
28. 28. The modified release solid oral dosage form of any one of embodiments 1-27, wherein a) the solid oral dosage form releases not more than 50% of pridopidine after 1 hour when the oral dosage form is placed in a basket apparatus in 500mL of HCl 0.1N at a temperature of 37°C rotating at 100 revolutions per minute; b) the solid oral dosage form releases not more than 75% of pridopidine after 3 hours when the oral dosage form is placed in a basket apparatus in 500mL of HCl 0.1N at a temperature of 37°C rotating at 100 revolutions per minute for 120 minutes and then in buffer phosphate having a pH 6.8, for 12 hours; or c) the solid oral dosage form releases not less than 80% of pridopidine after 10 hours when the oral dosage form is placed in a basket apparatus in 500mL of HCl 0.1N at a temperature of 37°C rotating at 100 revolutions per minute for 120 minutes and then in buffer phosphate having a pH 6.8, for 12 hours.
29. 29. The modified release solid oral dosage form of any one of embodiments 1-27, wherein a) the solid oral dosage form releases not more than 30% of pridopidine after 2 hours when the oral dosage form is placed in a basket apparatus in 500mL of HCl 0.1N at a temperature of 37°C rotating at 100 revolutions per minute for 120 minutes and then in buffer phosphate having a pH 6.8, for 12 hours; b) the solid oral dosage form releases not more than 50% of pridopidine after 4 hours when the oral dosage form is placed in a basket apparatus in 500mL of HCl 0.1N at a temperature of 37°C rotating at 100 revolutions per minute for 120 minutes and then in buffer phosphate having a pH 6.8, for 12 hours; c) the solid oral dosage form releases not more than 65% of pridopidine after 6 hours when the oral dosage form is placed in a basket apparatus in 500mL of HCl 0.1N at a temperature of 37°C rotating at 100 revolutions per minute for 120 minutes and then in buffer phosphate having a pH 6.8, for 12 hours; or d) the solid oral dosage form releases not less than 75% of pridopidine after 12 hours when the oral dosage form is placed in a basket apparatus in 500mL of HCl 0.1N at a temperature of 37°C rotating at 100 revolutions per minute for 120 minutes and then in buffer phosphate having a pH 6.8, for 12 hours.
30. 30. The modified release solid oral dosage form of any of embodiments 1-29, wherein the dosage form is in the form of a tablet.
31. 31. The modified release solid oral dosage form according to any of embodiments 1-30, wherein the rate controlling excipient is a polymeric material.
32. 32. The modified release solid oral dosage form according to embodiment 31, wherein the polymeric material is selected from a group consisting of: hydrogenated castor oil, polyethylene oxide, ethyl cellulose hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinyl alcohol (PVA), vinyl alcohol polymer, polycrylates, polymethacrylates, ethyl acrylate-methyl methacrylate copolymers, glyceryl monostearate, and mixtures thereof.
33. 33. The modified release solid oral dosage form according to embodiment 31, wherein the rate controlling excipient is a combination of two or more polymeric materials, preferably wherein rate controlling excipient is a combination of at least a hydroxypropyl methylcellulose (HPMC) and hydrogenated castor oil .
34. 34. The modified release solid oral dosage form of any one of embodiments 31-32, wherein the polymeric material is Hydroxypropyl methylcellulose.
35. 35. The modified release solid oral dosage form of any one of embodiments 31-32, wherein the polymeric material is Hydrogenated Castor Oil.
36. 36. The modified release solid oral dosage form according to any of embodiments 1-35, wherein the total amount of the rate controlling excipients is from about 8% to about 70% of the total weight of the dosage form, from about 10% to about 50% of the total weight of the dosage form, or from about 20% to about 50% of the total weight of the dosage form, from about 30% to about 50% or from about 30% to about 40% of the total weight of the dosage form.
37. 37. The modified release solid oral dosage form of any one of embodiments 31-36, wherein the polymeric material is between 10% and 50%, between 20% and 50%, between 30% and 50%, between 30% and 40%, between 35% and 40%, at least 10%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, about 37%, about 38%, or about 40%, by weight of the solid oral dose form.
38. 38. The modified release solid oral dosage form of any one of embodiments 1-37, further comprising an ethylcellulose.
39. 39. The modified release solid oral dosage form according to embodiment 38, wherein the total amount of the ethylcellulose is from about 0.5% to about 10% of the total weight of the dosage form, from about 0.5% to about 7.2% of the total weight of the dosage form, from about 1.0% to about 5% of the total weight of the dosage form, from about 1.0% to about 3.0% of the total weight of the dosage form, from about 1.5% to about 3.0% of the total weight of the dosage form, or from about 1.5% to about 2.4% of the total weight of the dosage form.
40. 40. The modified release solid oral dosage form of embodiment 38, wherein the ethylcellulose is about 1.5% by weight of the solid oral dose form.
41. 41. The modified release solid oral dosage form of embodiment 38, wherein the ethylcellulose is about 2.4% or 2.9% by weight of the solid oral dose form.
42. 42. The modified release solid oral dosage form of any one of embodiments 31-41, wherein the polymeric material is hydroxypropyl methylcellulose, and wherein the hydroxypropyl methylcellulose is about 38% by weight of the solid oral dose form.
43. 43. The modified release solid oral dosage form of any one of embodiments 31-41, wherein the polymeric material is Hydrogenated Castor Oil, and wherein the hydrogenated castor oil is about 38% by weight of the solid oral dose form.
44. 44. The modified release solid oral dosage form of any one of embodiments 31-41, wherein the polymeric material is hydroxypropyl methylcellulose, wherein the hydroxypropyl methylcellulose is about 37% by weight of the solid oral dose form, and wherein the ethylcellulose is between about 1.5% and about 3.0% by weight of the solid oral dose form.
45. 45. The modified release solid oral dosage form according to any one of embodiments 1-44, wherein the weight ratio of the Pridopidine or the pharmaceutically acceptable salt thereof to the rate controlling excipient is from about 0.2:1 to about 1:1, preferably from about 0.3:1 to about 0.8:1, preferably about 0.5:1 to about 0.7:1.
46. 46. The modified release solid oral dosage form of any one of embodiments 1-45 further comprising a mucoadhesive.
47. 47. The modified release solid oral dosage form of embodiment 46, wherein the mucoadhesive is selected from the group consisting of water soluble or water insoluble hydrophilic polymers, polymers that have swellable networks, hydrogels, and polymers with groups that can cross-link with other polymers or with a mucous membrane, preferably the mucoadhesive is polyethylene oxide.
48. 48. The modified release solid oral dosage form of any one of embodiments 1-47, wherein the Pridopidine or the pharmaceutically acceptable salt thereof comprises from about 15% to about 60%, about 25% to about 50%, or about 25%, by weight of the dosage form.
49. 49. A pharmaceutical formulation comprising the modified release solid oral dosage form of any one of embodiments 1-48, and one or more pharmaceutically acceptable carriers or excipients.
50. 50. The pharmaceutical formulation according to embodiment 49, wherein the pharmaceutically acceptable carriers or excipients are selected from a group consisting of: binder, filler, plasticizer, glidant and lubricant and mixtures thereof.
51. 51. The pharmaceutical formulation according to embodiment 50, wherein the binder is selected from a group consisting of: starch, pregeletinized starch, polyethylene oxide, cellulose polymers, hydroxypropylmethyl cellulose, hydroxypropylcellulose, methylcellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol and mixtures thereof.
52. 52. The pharmaceutical formulation according to any one of embodiments 50-51, wherein the filler is selected from a group consisting of: microcrystalline cellulose, sugar spheres, lactose, sorbitol, dextrose, sucrose, mannitol, dibasic or tribasic calcium phosphate, calcium sulfate, starch, retalac and mixtures thereof.
53. 53. The pharmaceutical formulation of embodiment 52, wherein the filler is microcrystalline cellulose and is a silicified microcrystalline cellulose.
54. 54. The pharmaceutical formulation of embodiment 52, wherein the filler is lactose.
55. 55. The pharmaceutical formulation of any embodiments 52, wherein the filler is a mixture of microcrystalline cellulose and lactose, and wherein the microcrystalline cellulose and is a silicified microcrystalline cellulose.
56. 56. The pharmaceutical formulation of any one of embodiments 50-56, wherein the filler is between 5% and about 64% by weight of the solid oral dose form, between 10% and about 50% by weight of the solid oral dose form, between 15% and about 45% by weight of the solid oral dose form, between 20% and 40% by weight of the solid oral dose form, about 34% by weight of the solid oral dose form, about 16% by weight of the solid oral dose form, about 17 % by weight of the solid oral dose form or about 18% by weight of the solid oral dose form.
57. 57. The pharmaceutical formulation of embodiment 56, wherein the filler is a mixture of silicified microcrystalline cellulose and lactose and wherein silicified microcrystalline cellulose is about 16% by weight of the solid oral dose form and lactose is about 17% or about 18% by weight of the solid oral dose form.
58. 58. The pharmaceutical formulation according to any one of embodiments 50-57, wherein the plasticizer is selected from a group consisting of: polyethylene glycol, triethyl citrate, tributyl citrate, glycerin, dibutyl sebacate, triacetin, diethylphthalat and mixtures thereof.
59. 59. The pharmaceutical formulation according to any one of embodiments 50-58, wherein the glidant is selected from a group consisting of: starch, pregelatinized starch, silicone dioxide, colloidal silicone dioxide, talc and mixtures thereof.
60. 60. The pharmaceutical formulation according to embodiment 59, wherein the glidant is colloidal silicone dioxide.
61. 61. The pharmaceutical formulation according to any one of embodiments 50-60, wherein the glidant is between 0.2% and about 4% by weight of the solid oral dose form, between 0.4% and about 3% by weight of the solid oral dose form, or between 0.43% and about 2.0% by weight of the solid oral dose form.
62. 62. The pharmaceutical formulation according to any one of embodiments 50-61, wherein the glidant is between 1.7% and about 4% by weight of the solid oral dose form, between 1.7% and about 3% by weight of the solid oral dose form, between 1.7% and about 2.0% by weight of the solid oral dose form, between 1.7% and 1.8% by weight of the solid oral dose form, about 1.7% by weight of the solid oral dose form or about 1.8% by weight of the solid oral dose form.
63. 63. The pharmaceutical formulation according to any one of embodiments 50-62, wherein the lubricant is selected from a group consisting of: sodium stearyl fumarate, stearic acid, magnesium stearate, calcium stearate, zinc stearate, talc, glyceryl behenate, glyceryl monostearate, and mixtures thereof.
64. 64. The pharmaceutical formulation according to embodiment 63, wherein the lubricant is magnesium stearate.
65. 65. The pharmaceutical formulation according to any one of embodiments 50-64, wherein the lubricant is between 0.3% and about 4% by weight of the solid oral dose form, between 0.5% and about 3% by weight of the solid oral dose form, or between 1.1% and about 2.0% by weight of the solid oral dose form.
66. 66. The pharmaceutical formulation according to any one of embodiments 50-64, wherein the lubricant is between 1.7% and about 4% by weight of the solid oral dose form, between 1.7% and about 3% by weight of the solid oral dose form, between 1.7% and about 2.3% by weight of the solid oral dose form, between 1.8% and about 2.2% by weight of the solid oral dose form or about 2% by weight of the solid oral dose form.
67. 67. A modified release solid oral dosage form or pharmaceutical formulation according to any one of embodiments 1-66, for use in the treatment of Huntington's Disease, Parkinson's disease, iatrogenic and non-iatrogenic Parkinsonism, dyskinesias, dystonias, Tourette's disease, iatrogenic and non-iatrogenic psychoses and hallucinoses, schizophrenia disorder or schizophreniform disorder, mood and anxiety disorders, manodepressive illness, depression, obsessive-compulsive disease, a sleep disorder, autism spectrum disorder, ADHD, age-related cognitive impairment, abuse of alcohol and substances used as narcotics, Alzheimer's disease or Retts syndrome.
68. 68. A method of treating a subject afflicted with a condition selected from Huntington's Disease, Parkinson's disease, iatrogenic and non-iatrogenic Parkinsonism, dyskinesias, dystonias, Tourette's disease, iatrogenic and non-iatrogenic psychoses and hallucinoses, schizophrenia disorder or schizophreniform disorder, mood and anxiety disorders, manodepressive illness, depression, obsessive-compulsive disease, a sleep disorder, autism spectrum disorder, ADHD, age-related cognitive impairment, abuse of alcohol and substances used as narcotics, Alzheimer's disease and Retts syndrome, wherein the method comprises administering the modified release solid oral dosage form or pharmaceutical formulation of any of embodiments 1-66 to the subject in need thereof.
69. 69. A method of treating an individual afflicted with a neurodegenerative disease or a disease related to dopamine, comprising once daily administration of the modified release solid oral dosage form or pharmaceutical formulation of any one of embodiments 1-66.
70. 70. Use of a modified release solid oral dosage form or pharmaceutical formulation according to any one of embodiments 1-66, for the manufacture of a medicament for treating a subject afflicted with Huntington's Disease, Parkinson's disease, iatrogenic and non-iatrogenic Parkinsonism, dyskinesias, dystonias, Tourette's disease, iatrogenic and non-iatrogenic psychoses and hallucinoses, schizophrenia disorder or schizophreniform disorder, mood and anxiety disorders, manodepressive illness, depression, obsessive-compulsive disease, a sleep disorder, autism spectrum disorder, ADHD, age-related cognitive impairment, abuse of alcohol and substances used as narcotics, Alzheimer's disease or Retts syndrome.
71. 71. The modified release solid oral dosage form or pharmaceutical formulation of any one of embodiments 1-66 wherein the modified release solid oral dosage form or pharmaceutical formulation is adapted for once daily administration.

Claims

A modified release solid oral dosage form comprising a therapeutically effective amount of Pridopidine or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable rate controlling excipient, wherein the rate controlling excipient is a polymeric material selected from hydrogenated castor oil, polyethylene oxide, ethyl cellulose hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinyl alcohol (PVA), vinyl alcohol polymer, polycrylates, polymethacrylates, ethyl acrylate-methyl methacrylate copolymers, glyceryl monostearate, and mixtures thereof, wherein the total amount of the rate controlling excipient is from about 30% to about 50% by weight of the dosage form.
The modified release solid oral dosage form of claim 1, wherein the pharmaceutically acceptable salt of Pridopidine is hydrochloride salt.
The modified release solid oral dosage form of any one of claims 1-2, wherein the dosage form is in the form of coated or uncoated pellets or mini tablets.
The modified release solid oral dosage form of any one of claims 1-2, wherein the dosage form is in the form of a tablet for oral administration, wherein the tablet contains disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and/or melting agents.
The modified release solid oral dosage form of claim 4, wherein the tablet further contains an inert carrier, wherein the inert carrier is xylose, gelatin or agar.
The modified release solid oral dosage form of claim 4, wherein the tablet further contains a binder, wherein the binder is a natural or synthetic gum or wax.
The modified release solid oral dosage form of claim 6, wherein the natural or synthetic gums is acacia, tragacanth, or sodium alginate.
The modified release solid oral dosage form of any one of claims 4-7, further comprising a lubricant, wherein the lubricant is sodium oleate, sodium stearate, sodium benzoate, or sodium acetate.
A modified release solid oral dosage form according to any one of claims 1-8, for use in the treatment of Huntington's Disease, Parkinson's disease, iatrogenic and non-iatrogenic Parkinsonism, dyskinesias, dystonias, Tourette's disease, iatrogenic and non-iatrogenic psychoses and hallucinoses, schizophrenia disorder or schizophreniform disorder, mood and anxiety disorders, manodepressive illness, depression, obsessive-compulsive disease, a sleep disorder, autism spectrum disorder, ADHD, age-related cognitive impairment, abuse of alcohol and substances used as narcotics, Alzheimer's disease or Rett syndrome.
The modified release solid oral dosage form for use in the treatment of Huntington's Disease according to claim 9, wherein the modified release solid oral dosage form when administered to human patient afflicted with Huntington's Disease shows reduced frequency of adverse events compared to b. i. d administration of an immediate release solid oral dosage.
The modified release solid oral dosage form for use according to claim 9 or 10, wherein the modified release solid oral dosage form is administered once daily.